Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:23]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[N:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=4)[CH2:21][CH3:22])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN.C1COCC1.C[CH2:49][N:50](C(C)C)C(C)C>CN(C=O)C.[Cl-].[NH4+]>[CH3:32][S:29]([C:27]1[CH:28]=[C:23]([C@@H:20]([NH:19][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:21][CH3:22])[CH:24]=[C:25]([NH:50][CH3:49])[N:26]=1)(=[O:30])=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(OS(=O)(=O)C(F)(F)F)nc(S(C)(=O)=O)c1
Agent: CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(NC)nc(S(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-6-methanesulfonyl-pyridin-2-yl ester (0.08 g, 0.13 mmol) in DMF (2 mL) was added a 2.0 M solution of methylamine in THF (0.150 mL, 0.30 mmol) followed by DIPEA (0.05 mL, 0.3 mmol). After 16 hours, the mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated onto silica gel. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[O:17]([CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:26]([CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:28])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)CCOc1ccccc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)CCOc3ccccc3)c2)cc1Cl
Yield: 22.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 2-phenoxy-ethanesulfonyl chloride (21.14 mg, 96 μmol, 1.1 eq). The product was purified by preparative TLC, the plate was eluted with dichloromethane/methanol 95/5, to give N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2-phenoxyethanesulfonamide (8.1 mg, >95% purity, yield: 22.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>ClCCl>[CH3:19][Si:20]([CH3:22])([CH3:21])[N:1]([CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: CO[Si](CCCN)(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[Si](CCCN([Si](C)(C)C)[Si](C)(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Aminopropyltrimethoxysilane (0.398 mol) and triethylamine (100 mL) were dissolved in dichloromethane (200 mL) in a round-bottom flask and trimethylsilyl chloride (0.800 mol) was added in a dropwise manner. After the addition was completed, the mixture was stirred at room temperature for 24 hours. Upon completion of reaction, N,N-bis(trimethylsilyl)aminopropyltrimethoxysilane (yield: 89%) was obtained through concentration under reduced pressure and fractional distillation. 1H and 13C NMR spectroscopic data of the purified N,N-bis(trimethylsilyl)aminopropyltrimethoxysilane are as follows.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:52](Cl)([O:54]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@H:14]([CH3:15])[N:16]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])[C:52](=[O:54])[NH:39]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)N[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine (8.0 mg, 0.0135 mmol) in CH2Cl2 (2 mL) was cooled to 0° C. and DIPEA (14 μL, 0.081 mmol) was added followed by triphosgene (2 mg, 0.00657 mmol). The reaction was stirred at 0° C. for 30 min and then diluted with EtOAc (30 mL). The reaction was washed with saturated NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 40% EtOAc/hexanes afforded (4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one. Rf=0.24 (40% EtOAc/hexanes). LCMS=619.2 (M+1)+. 1H NMR (CD2Cl2, 600 MHz; atropisomers present) δ 6.91-7.84 (m, 9H), 3.84-4.94 (m, 4H), 3.64-3.80 (m, 4H), 2.88 (m, 1H), 1.18-1.26 (m, 6H), 0.27-0.42 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28]OS(C)(=O)=O)[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[C-:43]#[N:44].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][C:43]#[N:44])[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CC#N)c2)c1CCC(=O)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-methanesulfonyloxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.51 g, 3.74 mmol) in DMF (40 mL), KCN (292 mg, 4.48 mmol) was added and stirred a 60° C. overnight. The reaction was diluted with EtOAc (250 mL) washed with water (100 mL×2), brine (50 mL), dried with Na2SO4. Concentration under reduced pressure provided an oil. Flash column chromatography (30% EtOAc/Hex) provided a light yellow oil (1.19 g, 53% yield). 1H NMR (CDCl3): δ 7.08 (t, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.17-4.06 (m, 4H), 4.01-3.91 (m, 4H), 3.68 (s, 2H), 2.97 (dd, 2H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].Cl.Cl.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][O:43][NH2:44].C([O-])(=O)C.[Na+]>CO>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][O:43][N:44]=[C:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=2)[C@H:9]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10]1
Reactant: CC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: CN(C)CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)=NOCCN(C)C
Yield: 104 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-yl)piperazine (255 mg), O-[2-(dimethylamino)ethyl]hydroxylamine dihydrochloride (89 mg), sodium acetate (catalytically), and methanol (10 mL) was heated under reflux for 2 h. The solvent was removed in vacuo, and the residue was treated with dichloromethane and NAOH (aq, 2N). The layers were separated, the organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford 1-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone O-[2-(dimethylamino)-ethyl]oxime 0.31 g (>95%) as an E/Z mixture. Rf 0.26 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH:58]1[CH2:61][CH:60]([C:62]#[N:63])[CH2:59]1>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]([N:58]1[CH2:61][CH:60]([C:62]#[N:63])[CH2:59]1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(C(=O)N4CC(C#N)C4)n3Cc3ccccc3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.010 g, 0.034 mmol, Example 58, Step 4) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.023 g, 0.060 mmol). After stirring for 2 minutes, azetidine-3-carbonitrile hydrochloride (0.012 g, 0.10 mmol, PharmaBlock) was added. When the reaction was determined complete by LCMS, the mixture was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (6 mg, 50%).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)CC(C)C.[CH2:35]([O:37][CH2:38][C@H]1CC[C@H](N)CC1)[CH3:36].COCC1CCC(N(CCC(C)C)C(=O)NC2SC(SCC(O)=O)=CN=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:35]([O:37][CH2:38][C@H:4]1[CH2:3][CH2:2][C@H:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5]1)[CH3:36]
Reactant: CCOC[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COCC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CCOC[C@H]1CC[C@H](N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-ethoxymethyl-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>[Cl:10][C:3]1[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: Cc1c(F)ccc(Br)c1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: Cc1c(F)ccc(C#N)c1Cl
Yield: 42 %

Procedure:
3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) was charged in a vial, DMF (1 mL) added, and the mixture irradiated for 150 sec at 200° C. in a microwave oven. Diethyl ether (30 ml) was added and the reaction mixture washed with magnesium sulphate (4% solution, 3×20 mL) followed by brine (20 mL). The organic layer was dried and evaporated. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (55 mg, 42%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][C:16]1([CH3:23])[O:20][C@@H:19]([CH2:21][OH:22])[CH2:18][O:17]1.C(N(CC)CC)C.C(OCC)(=O)C>O>[CH3:15][C:16]1([CH3:23])[O:20][C@@H:19]([CH2:21][O:22][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:18][O:17]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OC[C@H](COS(=O)(=O)c2ccc3ccccc3c2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 53 parts of 2-naphthalenesulfonyl chloride, 30 parts of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol, 70 parts of N,N-diethylethanamine and 180 parts of ethyl acetate was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromotography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 62.8 parts (85.8%) of (R)-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl]2-naphthalenesulfonate (interm. 9).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([C:13]1[O:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:9]([C:13]1[O:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C=Cc1ccc(C(C)(C)C)o1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)o1
Yield: 22.8 %

Procedure:
Sodium hydride (7.09 g-50% suspension in oil, 0.148 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (52.74 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-furancarboxaldehyde (22.46 g, 0.148 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether) to give (5-t-butylfuran-2-yl)-ethylene (11.03 g, 50%). Ethyl diazoacetate (4.45 g, 0.039 mol) in dry dichloromethane (70 ml) was added dropwise to a solution of (5-t-butylfuran-2-yl)-ethylene (5.85 g, 0.039 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (30 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give ethyl 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylate (2.1 g, 23%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][N:8]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[K+].[K+]>CO>[CH3:17][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-nitro-2H-pyrazole-3-carboxylic acid (524, 10.0 g, 0.0637 mol) in methanol (100.0 mL) was added concentrated sulfuric acid (1.00 mL, 0.0180 mol). The reaction was stirred at room temperature overnight. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (525, 1.5 g, 13.8%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH2:31][CH3:32])[N:19]=2)=[C:9]1[CH3:33])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:34])=[O:5])[C:9]=2[CH3:33])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[CH2:31][CH3:32]
Reactant: CCCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCN1N=C(c2c(C)n(CC(=O)O)c3ccc(F)cc23)c2ccccc2S1(=O)=O

Procedure:
[3-(2-Propyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.10 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H), 7.47 (m, 2H), 6.97 (m, 2H), 4.57 (s, 2H), 3.86 (t, 2H), 2.23 (s, 3H), 1.84 (m, 2H), 0.92 (t, 3H) ppm. MS calculated for C21H20FN3O4S—H: 428, observed: 428.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:20]([NH:24][CH2:25][C:26]#[N:27])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([N:24]([CH2:25][C:26]#[N:27])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCCCNCC#N
Product: CCCCN(CC#N)C(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.37 g, 1.4 mmol) and (n-butylamino)acetonitrile (0.48 g, 4.2 mmol) according to the procedure shown for Example 154 to give 0.52 g of an amber gum; MS (ES) m/z: 358.3 (MH+); HRMS (ES) Calcd. for C20H28N3O3 (MH+): 358.2125, Found: 358.2120.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:28][CH2:29][N:30]([CH3:35])[CH2:31][CH2:32]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
To a mixture of 0.030 g (0.06 mmole) of 4-(3-chloro-phenyl)-2-[6-(piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.23), 0.0095 mL (0.13 mmole) of 37% aqueous formaldehyde solution, 0.0041 mL (0.070 mmole) of acetic acid and 2.1 mL of methanol-dichloromethane (2:5) was added 0.019 g (0.090 mmole) of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was diluted with dichloromethane and ethyl acetate, washed with aqueous 1M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol-dichloromethane to give 0.015 g of 4-(3-chloro-phenyl)-2-[6-(1-methyl-piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.24). MH+/Z=482
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.CC1(C)[O:44][C@@H:43]([CH2:45][N:46]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=[N:47]2)[CH2:42][O:41]1>>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][N:46]1[CH:50]=[C:49]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][CH:21]=4)[N:10]=3)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=2)[CH:48]=[N:47]1
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 101A). After Suzuki reaction and SPE pre-purification, the dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was purified by MDP. MS (ES+): m/z 678.38 (100) [MH+] HPLC: tR=0.87 min (UPLC, purity).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:9]=2[O:8][C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(C)ccc2oc1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1C(=O)Oc2ccc(C)cc2C1c1ccccc1
Yield: 82.8 %

Procedure:
To a solution of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester (15.0 g) in acetic acid (150 ml) was added 10% palladium-carbon (3.0 g), followed by stirring at 80° C. in a hydrogen atmosphere (4 to 5 atm) for 4.5 hours. After the catalyst was filtered off, the filtrate was distilled to remove the solvent, followed by treatment of the residue with isopropyl ether, to yield 3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (12.5 g).
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[Br:11][C:12]1[S:16][C:15](C=O)=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15](=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:14][CH:13]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CCOP(=O)(CN)OCC
Product: CCOP(=O)(CN=C1CC=C(Br)S1)OCC
Yield: 100 %

Procedure:
Starting from 16.7 g. (0.1 mol) diethyl aminomethylphosphonate and 19.1 g. (0.1 mol) 5-bromothien-2-aldehyde and following a procedure identical to that described in Example 1, 34 g. (yield: 100%) of the desired product are obtained in the form of a yellow oil.