Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(Cl)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(Cl)nc2)n1
Reaction time: 24 h
Yield: 98.7 %

Procedure:
A solution of 4-(2-(6-chloropyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (70 mg, 0.126 mmol) in TFA (10 mL) was heated to 80° C. After 24 h, the mixture was concentrated to a slurry. Water (5 mL) was added, followed by the addition of Na2CO3 in batches until the pH was basic. The mixture was filtered and the solid was washed with water, then MeOH, to give the product as a brown solid (39 mg). LCMS (ES, pos.): calcd for C14H12ClN7: 313.1. found: 314.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H); 8.87 (d, J=2.74 Hz, 1H); 8.82 (dd, J=7.83, 1.76 Hz, 1H); 8.48 (dd, J=8.80, 2.74 Hz, 1H); 8.39 (dd, J=4.50, 1.76 Hz, 1H); 7.92 (br. s., 1H); 7.78 (br. s., 1H); 7.46 (d, J=8.61 Hz, 1H); 7.01 (dd, J=7.83, 4.70 Hz, 1H); 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH2:6][O:7][CH2:8][CH3:9])[CH3:2].Cl.[NH2:12][OH:13]>>[CH2:1]([O:3][CH2:4][C:5](=[N:12][OH:13])[CH2:6][O:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCOCC(=O)COCC
Reactant: NO
Agent: Cl
Product: CCOCC(COCC)=NO

Procedure:
1,3-Diethoxy-propan-2-one oxime was prepared from 1,3-diethoxy-propan-2-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (1H, s), 4.18 (2H, s), 3.96 (2H, s), 3.41 (4H, quin, 7.0 Hz), 1.10 (6H, q, 7.1 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:48])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]4[N:34]=[CH:33][C:32]5=[CH:35][CH:36]=[C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=6[O:44][CH3:45])[N:31]5[N:30]=4)=[C:24]([O:46][CH3:47])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:47][O:46][C:24]1[CH:23]=[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:48])[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[NH:28][C:29]1[N:34]=[CH:33][C:32]2=[CH:35][CH:36]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[N:31]2[N:30]=1
Reactant: COc1cc(C2CCN(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCN(CC(=O)N3CCNCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into an 8-dram vial Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (170 mg, 0.46 mmol), 4-{2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester (223 mg, 0.516 mmol), N,N-Diisopropylethylamine (250 uL, 1.4 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol). The reaction mixture was heated at 100° C. overnight. After 18 h, the mixture was cooled to RT and the product was purified by flash chromatography (ISCO, 40 g column, EtOAC-MeOH 95:5). The product was obtained as a syrup (156 mg, 52%). MS: 656 (M+H). The product was subjected to the BOC deprotection step. 4-[2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.23 mmol) was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (10 mL, 200 mmol). The mixture was stirred at RT. After 3 days, solvent was removed and the product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-1-piperazin-1-yl-ethanone, was purified by reverse phase liquid chromatography (Gilson) as a brown solid (61 mg, 48%, —85% pure). LCMS (E/I+) 556 (M+H). NMR 1H (DMSO-d6)-9.6 (br s, 1H), 9.02 (br s, 2H), 8.95 (s, 1H), 7.07 (d, 1H, J=8.27 Hz), 7.82 (d, 1H, J=6.44 Hz), 7.64 (s, 1H), 7.46 (m, 1H), 7.21 (d, 1H, J=8.37 Hz), 7.10 (m, 1H), 6.96 (m, 2H), 6.90 (s, 1H), 6.71 (d, 1H, J=8.34 Hz), 4.35 (m, 2H), 4.2-3.0 (series of m and s along with water peak, 18H), 2.84 (m, 1H), 2.08-1.99 (m, 4H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:48]([CH3:55])=[C:49]([CH:52]=[CH:53][CH:54]=3)[C:50]#[N:51])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[C:48]=3[CH3:55])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(C#N)c2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Sodium hydride (60% in oil) (92 mg, 2.30 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (500 mg, 1.04 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (282 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane. No separation was achieved. The column was repeated with a 0-10% MeOH/DCM gradient. Still no separation! Mixed fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (313 mg, 42.1%). m/z (ES+) (M+H)+=712.63; HPLC tR=3.85 min.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[N:30])[C:22](=O)[C:21]12OCCC[O:34]1)(=[O:17])=[O:16])C1C=CC=CC=1.N.C1COCC1>[Ni].CCO>[OH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][N:30]=[C:22]3[C:21](=[O:34])[C:20]=2[CH:19]=1)(=[O:17])=[O:16]
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)ccc21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4CO)ccc3N2C1
Temperature: 132 °C
Yield: 84.3 %

Procedure:
A mixture of 3-[5′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]-2,2-dimethylpropanenitrile (3.00 g, 5.56 mmol), wet Raney Nickel (3.18 g) in 2M EtOH.NH3 (180 mL) and THF (30 mL) was hydrogenated at 54 lb/in2 H2 for 22 hr. The reaction was filtered through Sulka Floc and the filtrate was poured into a steel pressure vessel and heated to 132° C. for 18 hr. After cooling to room temperature the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/0.5) to give the title compound as a white solid (1.77 g, 60% ). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Br[CH:22]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:23](Cl)=[O:24].C1(CC(Cl)=O)CCCC1>ClCCl>[CH:26]1([C:22]2[N:3]3[C:4]([CH3:14])=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[N:1][C:23]=2[OH:24])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1nnc(-c2ccccc2)c(N)n1
Reactant: O=C(Cl)C(Br)C1CCCC1
Agent: O=C(Cl)CC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Temperature: 120 °C

Procedure:
To a solution of 5-amino-3-methyl-6-phenyl-[1,2,4]triazine (0.2 g, 1.07 mmol) in dichloromethane (20 ml) was added pyridine (0.104 ml, 1.28 mmol) followed by dropwise addition of 2-bromo-2-cyclopentylacetyl chloride (0.266 ml, 1.18 mmol; prepared from cyclopentylacetyl chloride by the method of Gleason, Tetrahedron Lett., 1970, 39, 3431). The reaction mixture was stirred for 18 h after which time the dichloromethane was evaporated in vacuo. The residue was dissolved in t-butanol (20 ml) to which was added triethylamine (1 ml) and sodium iodide (0.010 g) and the resultant mixture was heated at 120° C. for 18 h. The n-butanol was evaporated in vacuo and the residue was purified by flash chromatography (SiO2; 60% EtOAc in hexanes) to afford the title compound (0.178 g). δH (400 MHz; d6-DMSO) 1.40-2.20 (8H, m), 2.71 (3H, s), 3.65 (1H, m), 7.49 (3H, m), 8.05 (2H, m). m/z (ES+) 295 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=3[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1

Procedure:
To a solution of 4-(5-cyano-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.2 g, 10 mmol) in dioxane (13 mL) was added a solution of HCl in dioxane (25%, 14.3 mL). The resulting precipitate was filtered to give the title compound.
Reaction SMILES: C(NCC)C.O.[CH2:7]([O:9][C:10](=[O:31])[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([Cl:22])[CH:21]=1)[C:12](O)=O)[CH3:8].C=O>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:31])[C:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([Cl:22])[CH:21]=1)=[CH2:12])[CH3:8]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: O
Solvent: CCNCC
Product: C=C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.3 %

Procedure:
Diethylamine (3.67 ml, 3.67 mmol) was added dropwise followed by water (2.5 ml) and CH2Cl2 (2.5 ml) to a mixture of 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.40 g, 3.64 mmol) and 37% aq. solution of formaldehyde (0.29 ml, 3.75 mmol) in CH2Cl2 (2 ml) at 0° C. The mixture was stirred for 20 h at room temperature and then poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3, dried and concentrated under reduced pressure. Flash chromatography (1-2.5% methanol in CH2Cl2) yielded 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-acrylic acid ethyl ester 0.81 g (65%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:19])[CH:11]=[CH2:12]>>[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[CH3:9])[C:14]1=[O:19])[CH:11]=[CH2:12]
Reactant: C=CCC1CCCNC1=O
Reactant: Cc1cc(N)ccc1I
Product: C=CCC1CCCN(c2ccc(N)cc2C)C1=O

Procedure:
Analogously to the process described under example 93A, 2.68 g (11.5 mmol) of 4-iodo-3-methylaniline and 2.0 g (14.3 mmol) of the compound from example 96A are used to obtain, after preparative HPLC, 1.31 g (47% of theory) of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:35])[C:16]([N:21]3[CH2:26][CH2:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)([OH:27])[CH2:23][CH2:22]3)=[CH:17][O:18]2)=[CH:13][C:12]=1[CH3:36])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C@H:15]([OH:35])[C@H:16]([N:21]3[CH2:26][CH2:25][C:24]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)([OH:27])[CH2:23][CH2:22]3)[CH2:17][O:18]2)=[CH:13][C:12]=1[CH3:36])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc2c(=O)c(N3CCC(O)(c4ccc(F)cc4)CC3)coc2cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1OCc1ccccc1)OC[C@@H](N1CCC(O)(c3ccc(F)cc3)CC1)[C@H]2O
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
A mixture of sodium borohydride (0.25 g, 6.61 mmol) and ethanol (5 mL) was stirred 10 min and then 7-benzyloxy-6-methyl-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one (0.30 g, 0.653 mmol in 20 mL of ethanol and 15 mL of tetrahydrofuran) was added. The reaction was stirred at ambient temperature overnight. Additional sodium borohydride (0.12 g) was added and stirring was continued over the weekend. The reaction was quenched with water and concentrated. The residue was triturated with water and filtered to give a solid which was a 2:1 mixture of starting material and product. This material was stirred with hot ethanol and filtered. The solid which was collected weighed 0.2 g and was pure starting material which could be recycled in this reduction step. The ethanol filtrate was concentrated to afford 0.113 g of (3R*,4S*)-7-benzyloxy-6-methyl-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4-ol which had: mp 201-202° C. This material was carried directly to the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)[CH2:4]1>CO.[Pd]>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:4]1
Reactant: COC1CN(c2ccc([N+](=O)[O-])nc2)C1
Agent: [Pd]
Solvent: CO
Product: COC1CN(c2ccc(N)nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 323a (1.5 g, 7.17 mmol) in methanol (150 mL) was added 10% Pd/C (150 mg). The system was evacuated and then refilled with H2. After stirring at room temperature for 2 h, the mixture was filtered. The filtrate was concentrated under reduced pressure to afford 323b as a yellow oil (1.2 g, 93%), which was used in next step without further purification. MS-ESI: [M+H]+ 180.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23]O)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])=[N:21][CH:22]=1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: OCc1ccc(Br)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(Br)cn1)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.1 %

Procedure:
To a stirred solution of 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1, 110 mg) in tetrahydrofuran (2.5 mL) were added (5-bromo-pyridin-2-yl)-methanol (CAS [88139-91-7], 92 mg), triphenylphosphine (129 mg) and diethyl azodicarboxylate (88 mg). The mixture was stirred for 48 h at r.t. The solvent was evaporated under reduced pressure and the product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-(5-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (106 mg) as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH:19]([CH3:21])[CH3:20]>CC(=O)CC>[CH:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)Oc1ccc(C=O)cc1

Procedure:
A mixture of 4-hydroxybenzaldehyde (20 g), anhydrous potassium carbonate (25 g), potassium iodide (0.5 g) and 2-iodopropane (27 g) in 2-butanone (300 ml) was heated overnight, under reflux, with stirring, cooled, filtered and evaporated to dryness. The residue was dissolved in diethyl ether, washed with aqueous sodium hydroxide and brine, dried (magnesium sulphate), filtered and evaporated to dryness. Distillation of the residue gave the title compound, bp 108°-112°/3 mm as an oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cn1nc(-c2ccc(OC)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(-c3ccccc3)n(CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
30.8 g of (3-(4-methoxy-phenyl)-5-phenyl-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 140 mL dioxane and a solution of 0.8 g LiOH in 140 mL of water was added. The mixture was stirred for 4 h at RT. The mixture was acidified with HCl-solution and the precipitate was filtered to give 9.0 g of the desired product as mixture of isomers. These isomers were separated by HPLC chiral (method 1; solvent MeOH: DCM=1:1, concentration: 90 mg/mL). Rt: 1.26 min (method A) and 1.24 min., (M+H)+: 310
Reaction SMILES: CS(O[CH2:6][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH3:8])(=O)=O.CC(NC(=O)OC(C)(C)C)(C)COC1C=CC=CC=1.[CH3:37][CH:38]([CH3:41])[CH2:39][SH:40]>>[CH3:8][C:7]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:9])[CH2:6][S:40][CH2:39][CH:38]([CH3:41])[CH3:37]
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(C)CS
Agent: CC(C)(COc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)CSCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
1,1-Dimethylethyl {1,1-dimethyl-2-[(2-methylpropyl)thio]ethyl}carbamate (D276) was prepared from 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) in an analogous manner to 1,1-dimethylethyl [1,1-dimethyl-2-(phenyloxy)ethyl]carbamate (D274) using 2-methyl-1-propanethiol instead of phenol.
Reaction SMILES: Cl.CO.C(O[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)=[O:10])(C)(C)C.[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[CH:19]1([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:13]3[CH:12]=[CH:17][CH:28]=[C:27]4[C:14]=3[NH:15][C:31]3[CH:21]=[CH:20][CH:19]=[CH:18][C:30]=3[O:29]4)=[O:10])[CH2:17][CH2:16]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCCCCCC2)CC1
Agent: Cl
Solvent: CO
Product: O=C(NC1CCN(CC2CCCCCCC2)CC1)c1cccc2c1Nc1ccccc1O2
Reaction time: 18 h

Procedure:
15 ml of 10% HCl-methanol solution and 15 ml of diethyl ether were added to 1.66 g of 4-t-butoxycarbonylamino-1-cyclooctylmethylpiperidine, followed by stirring for 18 hours. The solvent was distilled off under reduced pressure, the obtained residue was washed with diethyl ether, and 1.44 g of the title compound as a white solid was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)#[N:16]
Reactant: CSc1nccc(-c2[nH]ncc2I)n1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CSc1nccc(-c2[nH]ncc2C#N)n1

Procedure:
A solution of 4-(4-Iodo-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (4-2, 710 mg, 2.23 mmol, 1 equiv), zinc cyanide(157 mg, 1.34 mmol, 0.6 equiv), 1,1′-bis(diphenylphosphino)ferrocene (297 mg, 0.54 mmol, 0.24 equiv), and tris (dibenzylideneacetone)dipalladium(0) (204 mg, 0.22 mmol, 0.1 equiv) in DMF (10 mL) was degassed and placed in a 105° C. oil bath. After 1 hour the reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting oil was purified by chromatographed. Elution with 5–25% EtOAc/CH2Cl2 gave 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (4-3) as a tan solid. LRMS m/z: Calc'd for C9H7N5S (M+H) 318.1. found 318.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1Cl
Product: CCC(C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(cyclopropylmethyl)amino]benzonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 349 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][CH2:9][C:8]=2[CH:15]=1)(=[O:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Na].C[Si](Cl)(C)C.[Br:31]Br>C1COCC1>[Br:31][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][CH2:9][C:8]=2[CH:15]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)COC(C)(C)O2
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 1 h

Procedure:
To the product of step (b) (23.4 g, 0.113 mol) in 600 mL of THF at −78° C. was added 135 mL of 1.0 M sodium hexamethyldisilazane in THF (Sigma-Aldrich). After 1 hour, trimethylsilyl chloride (15.8 mL, 0.124 mol) was added. After another 30 minutes, bromine (5.82 mL, 0.113 mol) was added. After 10 minutes, the reaction was quenched by diluting the reaction mixture with diethyl ether and pouring it onto 500 mL of 5% aqueous Na2SO3 premixed with 500 mL of 5% aqueous NaHCO3. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an oil that solidified upon storage in the freezer.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@@H:8]2O)=[CH:4][CH:3]=1.C[CH2:13][N:14](CC)[CH2:15]C.CS(Cl)(=O)=O.CNC>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[N:14]([CH3:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: O[C@H]1CCc2ccc(Br)cc21
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCc2ccc(Br)cc21
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of (S)-6-bromo-indan-1-ol (1 mmol) and NEt3 (4 mmol) in dry THF (5 mL) was stirred at −15° C. under argon. A solution of methanesulfonyl chloride (2 mmol) in dry THF (1 mL) was cooled to −78° C. and then added slowly to the alcohol solution maintaining the temperature below 0° C. The reaction mixture was stirred for 2 h at −15° C. and then purged with dimethylamine gas (12 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Then, it was filtered to remove salts and solvent was evaporated. Crude was used in next step without further purification.