Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](O)(=[O:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[C:37]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16]1)(=[O:39])[CH3:38]
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (8.4 μl) was added, acetic acid (6.9 μl) and WSC.HCl (23 mg) were added thereto and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(O)ccc2-n2c(C)nnc21
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
2-[(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide (which may be prepared, for example, by reaction of Reference compound H with ethylamine) (0.424 g) was dissolved in DCM (8 ml) and cooled to −78° C. A solution of boron tribromide (0.945 ml) in DCM (2 ml) was added slowly to the reaction mixture. The reaction was stirred at −78° C. for 35 min under nitrogen and then at room temperature for 2.5 h. The reaction was quenched by adding a solution of ethanol (1 ml) in DCM (5 ml) dropwise. The solvent was evaporated and the residue was chromatographed (0-10% methanol:DCM) to give 2-[(4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a yellow solid. The aqueous layer was passed through a pre equilibrated Biotage 103 column, the organic content was eluted with methanol and the methanolic solution was evaporated to give a further quantity of 2-[(4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a yellow solid (total yield 271.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>C1COCC1>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[CH:4]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Clc1nc2ccccc2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(C(=O)OC(C)(C)C)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate (0.6 g, 2.4 mmol) in THF (10 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (0.44 g, 2.4 mmol) and stirred at this temperature for 15 minutes. To this solution was added 2-chlorobenzoxazole (2.4 mmol, 2.4 mL of a 1.0M solution). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was evaporated and purified by flash chromatography (0-15% ethyl acetate/hexanes) to give tert-butyl 4-[1-(1,3-benzoxazol-2-yl)-2-methoxy-2-oxoethyl]benzoate as a yellow oil. 1H NMR (600 MHz, DMSO-d6) δ 7.91 (d, J=8.21 Hz, 2H), 7.71 (m, 2H), 7.60 (d, J=8.21 Hz, 2H), 7.37 (m, 2H), 5.94 (s, 1H), 3.70 (s, 3H), 1.51 (s, 9H); ESIMS calcd 368.1 (M++H), found 368.1 (M++H).
Reaction SMILES: C([N:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([C:29]3[S:30][CH:31]=[C:32]([CH2:34][C:35]#[N:36])[N:33]=3)=[C:23]2[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([C:29]3[S:30][CH:31]=[C:32]([CH2:34][C:35]#[N:36])[N:33]=3)=[C:23]2[CH:22]=[N:21]1
Reactant: N#CCc1csc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1csc(-c2ccnc3[nH]ncc23)n1
Yield: 15.7 %

Procedure:
A solution of 2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]acetonitrile (83 mg, 0.1716 mmol) in DCM (3 ml) was treated with triethylsilane (0.5 ml) followed by TFA (0.5 mL). After 15 minutes the mixture was concentrated in vacuo and purified by column chromatography (70:9:1 DCM/MeOH/NH4OH) to give the product as a light tan solid (6.5 mg, 16% Yield). 1H NMR (DMSO, 400 MHz) δ 4.37 (2H, s), 7.72 (1H, d), 7.94 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s); MS (ES+) 242.00
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C=O)CCC=CC1>O>[CH:2]1(/[CH:1]=[N:8]/[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: Cc1ccccc1
Reactant: NCc1ccccc1
Agent: O=CC1CC=CCC1
Solvent: O
Product: C1=CCC(/C=N/Cc2ccccc2)CC1
Temperature: 112.5 °C

Procedure:
To a flask equipped with a Dean-Stark apparatus was added benzylamine (B) (97.3 g, 0.91 mol) and toluene (350 g). The mixture was warmed to 110-115° C. and 3-cyclohexene-1-carboxaldehyde (A) (100 g, 0.91 mol) was added over 1-1.5 h, while azeotropically removing water. After the addition was complete, toluene was distilled (approx. 100 mL) and then the reaction was cooled to 20-30° C. The resulting solution was approximately 40 w/w % (1) in toluene. The solution of (1) in toluene was carried forward without further isolation or purification. Typical assay: 99 area % purity (GC), retention time 15.3 min. 1H NMR (400 MHz, CDCl3) δ 7.78-7.75 (1H, m), 7.37-7.32 (2H, m), 7.30-7.26 (3H, m), 5.75-5.73 (2H, m), 4.62 (2H, s), 2.62-2.52 (1H, m), 2.31-2.23 (1H, m), 2.20-2.11 (3H, m), 2.00-1.93 (1H, m), 1.68-1.58 (1H, m).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][CH:35]=1)[CH2:12][N:13]1[CH2:17][C:16](=[O:18])[N:15]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])[CH:23]=2)[C:14]1=[O:32])(C(C)(C)C)(C)C.Cl>CO>[CH3:31][C:26]1[C:25]([CH2:24][N:22]2[CH:23]=[C:19]([N:15]3[C:16](=[O:18])[CH2:17][N:13]([CH2:12][C:11]4[CH:33]=[CH:34][CH:35]=[C:9]([OH:8])[CH:10]=4)[C:14]3=[O:32])[CH:20]=[N:21]2)=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)C2=O)cn1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(O)c3)C2=O)cn1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
1-(3-(tert-butyldimethylsilyloxy)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (Example 10-10b) (6.00 g, 12.11 mmol) was dissolved in methanol (100 mL) and treated with HCl (2.0 M solution in diethyl ether, 5 equivalents). The solution was refluxed for 2. The mixture was allowed to cool down to room temperature and the solvent was removed. The residue was triturated in toluene, filtered and recrystallized from ethanol at 4° C. to give 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (4.50 g, 11.80 mmol, 97%) as a white solid. 1H NMR (DMSO, 400 MHz): 2.15 (s, 3H), 2.39 (s, 3H), 3.97 (s, 2H), 4.43 (s, 2H), 5.18 (s, 2H), 6.68 (m, 3H), 7.12 (m, 1H), 7.80 (s, 1H), 8.17 (s, H), 9.41 (s, H). MS 382 (MH+).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.CON(C)[C:20](=[O:33])[CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:20](=[O:33])[CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)CCCN(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN(CCCC(=O)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
[(4-Bromobenzyl)oxy](tert-butyl)dimethylsilane (2.30 g, 7.64 mmol), a compound described in the literature (Eur. J. Org. Chem.; EN, 8, 2001, 1549), was dissolved in tetrahydrofuran (7.6 mL), a 1.6 M n-butyllithium-hexane solution (4.37 mL, 7.00 mmol) was added at −78° C., and the mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl {4-[methoxy(methyl)amino]-4-oxobutyl}methylcarbamate (1.65 g, 6.36 mmol), a compound described in the literature (Bio. Org. Med. Chem. 2004, 12, 5147-5160), in tetrahydrofuran (7.6 mL) was further added at −78° C., and the temperature was increased to room temperature. After the reaction was completed, a 1 N tetrabutylammonium fluoride-tetrahydrofuran solution (12.7 mL, 12.7 mmol) was added. Subsequently, 1 N hydrochloric acid was further added. A saturated aqueous sodium hydrogencarbonate solution was further added, the mixture was extracted with ethyl acetate, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=1:1→1:2, v/v) to give the title compound (1.29 g; yield, 48%) as a yellow oily substance.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B(O)O)=[CH:37][C:32]=2[O:31][CH2:30]1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:36]3[CH:35]=[CH:34][C:33]5[O:29][CH2:30][O:31][C:32]=5[CH:37]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(-c3ccc4c(c3)OCO4)cccc2[nH]1

Procedure:
This compound is synthesized from compound 194 (see example 156) and benzo[1,3]dioxol-5-yl-boronic acid analogously to the method described in Example 156.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][S:11](=[O:21])(=[O:20])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30].C(O)(=O)C[C:33](CC(O)=O)([C:35](O)=[O:36])[OH:34]>C(O)CO>[OH:34][CH2:33][CH2:35][O:36][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][S:11](=[O:21])(=[O:20])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: COc1ccccc1Oc1c(Cl)nc(SC)nc1NS(=O)(=O)NCc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)NCc2ccccc2)nc(SC)nc1OCCO
Temperature: 100 °C
Reaction time: 40 h

Procedure:
Benzylsulfamic acid [6-chloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-amide (1.75 g) was added to a solution of potassium tert.-butylate (1.87 g) in ethylene glycol (30 ml) and stirred at 100° C. for 40 h. The reaction mixture was poured onto water (120 ml), acidified with solid citric acid (1.9 g) and cooled to 0° C. The precipitate was filtered off, washed with water and dried at HV to give benzylsulfamic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-amide (Example 203). LC-MS: tR=4.70; [M+H]+=493.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][C:8]1([CH2:16][CH2:15][CH2:14]1)[CH2:7][CH2:6]2.Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=1)[C:8]1([CH2:14][CH2:15][CH2:16]1)[CH2:7][CH2:6]2
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1c(C)cc2c(c1C)CCC1(CCC1)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C)cc2c(c1C)CCC1(CCC1)N2Cc1ccc2ccccc2n1
Yield: 57.5 %

Procedure:
A mixture of 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinoline] (270 mg), 2-(chloromethyl)quinoline (626 mg), K2CO3 (528 mg) and sodium iodide (30 mg) in acetone (20 mL) was refluxed over night. After evaporation of the solvent, water was added to the residue and the aqueous solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The residue was purified by column chromatography (10% ethyl acetate/hexane), giving 6′-methoxy-5′,7′-dimethyl-1′-(quinolin-2-ylmethyl)-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinoline] as a light yellow solid (250 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:14])[CH3:15])([P:21](=[O:30])([O:22][CH:23]([CH3:25])[CH3:24])[O:26][CH:27]([CH3:29])[CH3:28])[F:10])[CH:5]=[N:6][CH:7]=3)=[CH:37][CH:38]=2)[CH:33]=[N:32]1
Reactant: OB(O)c1ccc2[nH]ncc2c1
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(Br)c1)P(=O)(OC(C)C)OC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(-c2ccc3[nH]ncc3c2)c1)P(=O)(OC(C)C)OC(C)C
Temperature: 80 °C
Reaction time: 36 h
Yield: 45 %

Procedure:
Tetraisopropyl (2-(5-bromopyridin-3-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (85 mg; 0.16 mmol), Pd(PPh3)4 (36.9 mg; 0.032 mmol) and (1H-indazol-5-yl)boronic acid (39 mg; 0.24 mmol) are added to the vial and the vial is capped with a septum. DME (4 mL) is added and the vial is flushed with argon, an aqueous solution of potassium carbonate (2.5 eq.) is added and the mixture is flushed again with argon. The reaction mixture is stirred at 80° C. for 36 h under an atmosphere of argon. The mixture was cooled to RT, diluted with EtOAc and filtered through Celite™, the Celite™ is washed three times with EtOAc/MeOH (1:1). The filtrate is deposited on silica gel and purified by column chromatography (on pre washed silica with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc and then to 50% MeOH in EtOAc. The pure product is isolated as a brown oil (41 mg, 45% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:13](O)(=[O:15])C>[C-]#N.[Na+].O=[Mn]=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:15][CH3:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=Cc1ccc2cnccc2c1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
290 mg of isoquinoline-6-carbaldehyde are dissolved in 40 ml of MeON, and firstly 450 mg of NaCN, then 210 μl of glacial acetic acid, and finally 3.5 g of MnO2 are added. The mixture is stirred at RT for 3 days, and the precipitate is filtered off and the filtrate is poured into a solution of 15 g of FeSO4 in 150 ml of water. Subsequently, the pH of the mixture is adjusted to 9 with Na2CO3 solution, the precipitate is filtered off, and the filtrate is extracted 3× with 150 ml of EA. Drying takes place over Na2SO4, and the solvent is removed in vacuo. 190 mg are obtained of a colorless oil, which in reacted without any further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N:15]=[C:16]=[S:17])=[C:4]([F:18])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25](OCC)=[O:26]>CCCCCC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N:15]2[C:25](=[O:26])[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[C:16]2=[S:17])=[C:4]([F:18])[CH:3]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Fc1cc(Cl)c(OCC2CC2(F)F)cc1N=C=S
Solvent: CCCCCC
Product: O=C1C2CCCCN2C(=S)N1c1cc(OCC2CC2(F)F)c(Cl)cc1F

Procedure:
2.9 g 4-Chloro-5-(2,2-difluorocyclopropylmethoxy)-2-fluorophenyl isothiocyanate was dissolved in 20 ml hexane and added dropwise to a solution of 1.5 ml ethyl piperidine-2-carboxylate in 10 ml hexane. The mixture heated under reflux for 2 hours. The solvent was removed and the residue was chromatographed on silica gel using a mixture of 3 parts hexane and 1 part ethyl acetate.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=O.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([O:19][N:20]=[C:3]1[C:4]2[CH:8]=[CH:7][S:6][C:5]=2[CH2:9][CH:2]1[OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOCc1ccccc1
Reactant: O=C1c2ccsc2CC1O
Agent: Cl
Solvent: c1ccncc1
Product: OC1Cc2sccc2C1=NOCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one (33.4 g, 0.216 mol) in pyridine (300 mL) was added O-benzylhydroxylamine hydrochloride (38.3 g, 0.240 mol) and the mixture was stirred at room temperature over weekend. The mixture was evaporated under reduced pressure and co-evaporated two times with toluene. Ethyl acetate was added and the organic phase was washed with 5% citric acid and brine. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. Yield. 55.1 g=98%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.O[CH:16]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH2:17][CH:18]=[CH2:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:16]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:17][CH:18]=[CH2:19])=[CH:10][CH:9]=1
Reactant: Oc1ccc(OC2CCCCO2)cc1
Reactant: C=CCC(O)c1ccc(C#N)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
4-(Tetrahydro-2H-pyran-2-yloxy)phenol (19.0 g; 0.1 mol) and 4-(1-hydroxy-3-butenyl)benzonitrile (17.8 g; 0.1 mol) was mixed in toluene, and cooled to 0° C. (under nitrogen). TBP (22.9 g; 0.11 mol) was added, followed by ADDP. The mixture was stirred at rt overnight, filtered, and evaporated. Purification by chromatography on silica gave 24 g (68.7%) of the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>C(OCC)(=O)C.[OH-].[Na+]>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([O:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)=[CH:3][CH:4]=[N:5]2
Reactant: Oc1ccc(F)cc1
Reactant: Clc1cc(Cl)c2c(Cl)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccnc3cc(Cl)cc(Cl)c23)cc1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 76.4 %

Procedure:
A mixture of 29.11 g of 4,5,7-trichloroquinoline and 16.84 g of 4-fluorophenol was heated to 160° C. After approximately 40 minutes, the molten solution solidified. The solid was dissolved in ethyl acetate and 2N NaOH. The organic layer was washed with base to remove excess phenol, then dried. Solvent was removed by reducing pressure, and the residue was purified by recrystallizing in heptane to produce 29.49 g of the title product. M.P. 105°-106° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=3[F:20])=[C:10]([C:21](OCC)=[O:22])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C1COCC1.C(Cl)Cl>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=3[F:20])=[C:10]([CH:21]=[O:22])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1-c1cc(F)c(F)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cnn(-c2ccccc2)c1-c1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 1-phenyl-5-(2,4,5-trifluorophenyl)-1H-pyrazole-4-carboxylate (459 mg, 1.325 mmol) in THF (5 mL) was added LAH (1.988 mL, 1.988 mmol as a 1 M THF solution) at room temperature and the reaction was then heated at 50° C. for 2 hours. The reaction was quenched with addition of 0.2 mL of water, 0.2 mL of 0.5 N NaOH and then 0.2 mL of water. The suspension was diluted with ether and was filtered through celite. Upon removal of the volatiles, the crude residue was purified by flash chromatography to afford an oil. The oil was then dissolved in 5 mL of CH2Cl2 and Dess-Martin periodinane (233.8 mg, 0.768 mmol) was added. The suspension was stirred at room temperature for 16 hours. The mixture was poured into EtOAc and was washed with brine. The organic phase was dried with Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography using a gradient of ethyl acetate/hexanes to afford the title intermediate as white solid.