Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH2:26]([O:25][C:23](=[O:24])/[CH:28]=[CH:2]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1)[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc(CO)cn2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc1
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl (3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate (3.65 g, 11.9 mmol) in dioxane (50 mL) was added manganese(IV) oxide (7.7 g, 89 mmol) and, (carbethoxymethylene)triphenylphosphorane (6.2 g, 17.8 mmol). After stirring for 18 hrs at 60, a resulting precipitate was filtered and the filtrate was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/5) to give tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.99 g, 89%).
Reaction SMILES: ClC1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[K+].[K+].BrC1N=C(CN2CCCC2=O)SC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH2:52][N:53]3[CH2:57][CH2:56][CH2:55][C:54]3=[O:58])[S:40][C:41]=2C2C=CC(S(N)(=O)=O)=CC=2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH2:52][N:53]3[CH2:57][CH2:56][CH2:55][C:54]3=[O:58])[S:40][CH:41]=2)=[CH:33][CH:32]=1
Reactant: NS(=O)(=O)c1ccc(-c2sc(CN3CCCC3=O)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1CCCN1Cc1nc(Br)cs1
Agent: OB(O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCCN1Cc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 97.5 °C
Yield: 86.6 %

Procedure:
(4-chlorophenyl) boronic acid (0.22 g, 1.42 mmol) and potassium carbonate (0.41 g, 2.97 mmol) were added to a solution of 1-((4-bromothiazol-2-yl)methyl)pyrrolidin-2-one (Step-1 of Compound 103, 0.31 g, 1.18 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.07 g, 0.06 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for lhr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.3 g, 86.6%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][C:9](O)=O.O.N>S(=O)(=O)(O)O>[Cl:6][CH2:7][CH2:8][C:9]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: O=C(O)CCCl
Reactant: NNC(N)=S
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nnc(CCCl)s1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Thiosemicarbazide (10 g, 111 mmol) is added in portions to a solution of 3-chloropropionic acid (10 g, 92 mmol) in concentrated sulfuric acid. The mixture is heated with stirring at 75° C. for 1 hour. After cooling to room temperature the reaction mixture id added slowly to water and the resulting solution is brought to pH 7 by addition of aqueous ammonia solution. The titled product precipitates as a yellow solid which is removed by filtration and dried.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C@@H:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:15]>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][C@H:14]([CH3:15])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:10]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (10 g, 59 mmol) and (R)-2-amino-3,3-dimethylbutane (353 mL of a 0.2M solution in absolute ethanol, 71 mmol) was stirred at room temperature for 24 hours. Another portion of (R)-2-amino-3,3-dimethylbutane (150 mL of a 0.2M solution in absolute ethanol, 30 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The slurry was filtered, and the filtrate concentrated under reduced pressure. The resulting solid was trituated with hexane:ethyl acetate (150:5 mL), then washed with hexane to give 9.78 g (74%) of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione as a white solid: 1H NMR: (DMSO-d6): δ 8.72 and 8.50 (two d, 1H, rotamers), 4.65 (m, 2H), 3.90 and 3.42 (two m, 1H, rotamers), 1.37 and 1.35 (two overlapping t, 3H, rotamers), 1.10 (two overlapping d, 3H, rotamers), 0.85 and 0.84 (two s, 9H, rotamers) ppm. IR (KBr): 3150, 2950, 1800, 1700 cm-1 ; MS (m/z): 225 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][CH2:9]2)=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([S:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:20]#[N:21]>>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([C:19]([S:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([OH:12])[CH:5]=3)[CH2:9]2)[C:20]#[N:21])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1O)CNC2
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Yield: 74.2 %

Procedure:
The procedure of Example 49 is used with 0.209 g of 2,3-dihydro-6-methoxy-1H-isoindol-5-ol (Example 105) and 0.57 g of α-(5-bromopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.5 g of the desired product as a gray foam. MS(Hi res): m/z Calcd for C31H36N2SO4 533.2474 Found 533.2460
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br

Procedure:
The title compound is prepared from 4-bromo-3,5-dimethylphenol and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 1): tR=1.35 min; Mass spectrum (ESI+): m/z=269 [M+H—H2O]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=3)[S:10][C:3]=12.[OH-].[Na+].Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[S:10][C:3]=12
Reactant: COC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylate (0.200 g, 0.62 mmole), prepared by the method described in PC10795A, section A, example 26, in EtOAc (5 ml) was added 1N aqueous NaOH solution (1.85 ml, 1.85 mmole). The reaction mixture was stirred at 50° C. for 1 h, cooled to room temperature, diluted with H2O (10 ml) and acidified with 1N HCl to pH˜2. The resulting solution was extracted with 10% MeOH in CH2Cl2 (5×10 ml), dried over MgSO4 and concentrated and dried under vacuum to give yellow solid (0.181 g, 98%). 1H NMR (300 MHz, DMSO-d6) □ 7.67 (1H, d, J=5.09 Hz) 8.41 (1H, s) 8.65 (1H, s) 8.71 (1H, bs); ESIMS (MH+): 309.95.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([NH:15][S:16]([CH:19]2[CH2:21][CH:20]2[CH2:22][O:23]CC2C=CC=CC=2)(=[O:18])=[O:17])=[C:8]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[C:7]=1[F:40].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:5][C:6]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([NH:15][S:16]([CH:19]2[CH2:21][CH:20]2[CH2:22][OH:23])(=[O:17])=[O:18])=[C:8]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[C:7]=1[F:40]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1CC1COCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1CC1CO
Temperature: -75 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
1M BCl3 solution in DCM (0.477 mL, 0.4777 mmol) was added dropwise to a solution of 2-benzyloxymethyl-cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzofuran-7-yl]-amide (0.150 g, 0.2388 mmol) in dry DCM (5 mL) at −75° C. and stirred for 1 hour at −75° C. The reaction mass was allowed to attain 20-35° C. and continued the stirring for 2 hours at same temperature. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was quenched with saturated sodium bicarbonate solution and then diluted with DCM (50 mL). The organic layer was separated, washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 0.070 g of the product (55% yield). 1H NMR (DMSO-d6, 300 MHz): δ 9.38 (s, 1H), 8.19 (d, 1H), 7.77 (bs. 1H), 7.52 (dd, 1H), 7.33 (d, 1H), 7.22 (d, 1H), 6.42-6.44 (m, 1H), 4.53 (t, 1H), 3.21-3.31 (m, 1H), 3.02-3.10 (m, 1H), 1.41-1.46 (m, 1H), 1.20 (m, 1H) 0.85-0.90 (m, 1H), 0.75-0.79 (m, 1H). LCMS: 96.82%, m/z=536.9 (M−1). HPLC: 94.75%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[NH2:10])=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28](=N)OCC)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:10][C:28]([C:27]3[CH:33]=[CH:34][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[N:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1
Reactant: NC(c1ccc(Cl)cc1)C(N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc([N+](=O)[O-])cc3)N2)cc1
Yield: 36.9 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine (200 mg, 0.685 mmol) and ethyl 4-methoxy-benzimidate hydrochloride (148 mg, 0.686 mmol) in ethanol (5 mL) was added triethylamine (0.11 mL, 0.79 mmol). The reaction mixture was heated at reflux for 12 h. The solvent was removed to give a clear oil. It was then taken in methylene chloride (2 mL) and aqueous sodium carbonate. The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated. Purification of the crude residue by Biotage flash chromatography eluting with 70% ethyl acetate in hexanes gave 4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5-dihydro-1H-imidazole (103 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:9](=[O:11])[C:8]3[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 5-aminoindole by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH:40]([CH3:49])[CH2:41][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: CC(Cl)C(=O)N1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OC(C)CN3CCCCC3)cc2)c1
Yield: 29.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphth alen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:34])[C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:34])[C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(C)[C@@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N,N-dimethylpiperidin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.53 (d, J=13.18 Hz, 1 H) 1.77 (m, J=16.10 Hz, 2 H) 2.10 (br. s., 1 H) 2.33 (s, 3 H) 2.57-2.89 (m, 6 H) 2.90-4.77 (m, 5 H) 7.63 (br. s., 1 H) 7.74 (t, J=7.54 Hz, 1 H) 8.09 (d, J=7.81 Hz, 1 H) 8.24 (br. s., 1 H) 8.35-8.66 (m, 2 H) 9.86 (br. s., 1 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:32][NH:31][CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:8]1[C:9]2[CH2:32][N:31]([CH3:33])[CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (400 mg, 0.94 mmol, example 106) was is dissolved in methanol (5 mL). Acetic acid (0.054 mL, 0.94 mmol) was added followed by formaldehyde (0.070 mL, 0.94 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (58.9 mg, 0.94 mmol) was added. LCMS analysis showed full conversion after 1 h. The solvent was evaporated under reduced pressure, the crude redissolved in methanol, filtered and purified by preparative HPLC yielding 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (74.0 mg, 17.60%). MS (ES+) m/z 441.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Cc1ccccc1)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)Cc4ccccc4)c23)C1
Yield: 70.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide (300 mg, 0.86 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (518 mg, 2.58 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(2-phenylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (320 mg, 70% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[O:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15]([N:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18]4)=[O:16])=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)N1Cc2ccccc2C1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-(1,3-dihydro-isoindol-2-yl)-ethanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[CH:10]=[CH2:11])=[O:4].C12BC(CCC1)CCC2.[OH:28]O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:8][C:9]=1[CH2:10][CH2:11][OH:28])=[O:4]
Reactant: C=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)OC
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1CCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-vinyl-thiophene-2-carboxylic acid methyl ester (5.35 g, 19.19 mmol) in tetrahydrofuran (220 mL) and cool to 0° C. Slowly add 9-borabicyclo[3.3.1]nonane (112 mL, 0.5 M, 56 mmol), warm the reaction to room temperature with stirring for 16 h. Cool the mixture to 0° C. and slowly add hydrogen peroxide (74 mL, 721 mmol) followed by 5 N sodium hydroxide (74 mL, 370 mmol). Add water (14 mL) and extract with ethyl acetate (3×150 mL). Dry the solution over Na2SO4, filter and evaporate. Purify by chromatography eluting with 50% ethyl acetate/hexane to afford 5.70 g (100%) of the title compound. LC-MS/ES m/z (35Cl) 296.7.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[CH2:12][C:13]#N)[CH2:3]1.[O:25]1CCCC1>[AlH](CC(C)C)CC(C)C.CCCCCC>[OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[CH2:12][CH:13]=[O:25])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]12O
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=O)CC[C@]12O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.50 g of 3β,14β-dihydroxy-5β-pregnane-21-nitrile in 500 ml of dry tetrahydrofuran, 105 ml of 1M i-Bu2AlH in hexane were added dropwise under nitrogen at 0° C. After 1 hr the reaction was quenched with aqueous citric acid (7.05 g in 32.5 ml of water) and stirred at room temperature for 1 hr. The mixture was then filtered through Celite and washed with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness to give 6.05 g of the title compound (II-b) partially in the internal hemiacetal form, as a white foam.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29]C(OC(C)(C)C)=O)[CH2:25]3)=[N:19][CH:20]=[C:21](Br)[CH:22]=2)(=[O:16])=[O:15])[CH2:10]1)C(=O)[O-])(C)C.[CH3:37][C:38]1([CH3:62])[CH2:47][CH2:46][C:45]2[N:44]=[CH:43][N:42]=[C:41]([N:48]3[CH2:54][C:53]4[CH:55]=[C:56](B(O)O)[CH:57]=[CH:58][C:52]=4[O:51][CH2:50][CH2:49]3)[C:40]=2[CH2:39]1>>[NH2:29][C@H:26]1[CH2:27][CH2:28][N:24]([C:18]2[C:17]([S:14]([N:11]3[CH2:12][CH2:13][C@H:9]([NH2:5])[CH2:10]3)(=[O:16])=[O:15])=[CH:22][C:21]([C:56]3[CH:57]=[CH:58][C:52]4[O:51][CH2:50][CH2:49][N:48]([C:41]5[C:40]6[CH2:39][C:38]([CH3:37])([CH3:62])[CH2:47][CH2:46][C:45]=6[N:44]=[CH:43][N:42]=5)[CH2:54][C:53]=4[CH:55]=3)=[CH:20][N:19]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(Br)cc2S(=O)(=O)N2CC[C@H](N(C(=O)[O-])C(C)(C)C)C2)C1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N6CC[C@H](N)C6)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl[(3S)-1-({5-bromo-2-[(3S)-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)pyrrolidin-1-yl]pyridin-3-yl}sulfonyl)pyrrolidin-3-yl]carbamate (reagent preparation 40) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (s, 1H), 8.55 (s, 1H), 8.53 (s, 1H), 7.74 (s, 1H), 7.52 (d, 1H), 7.01 (d, 1H), 5.12 (s, 2H), 4.47 (m, 2H), 4.32 (m, 3H), 4.22 (m, 1H), 4.05 (m, 2H), 3.85 (m, 1H), 3.74 to 3.56 (m, 5H), 2.85 (t, 2H), 2.59 (s, 2H), 2.35 (m, 2H), 2.22 (m, 2H), 1.70 (t, 2H), 0.93 (s, 6H); MS (EI) for C32H42N8O3S: 619 (MH+).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1CCN(C2CCNCC2)C1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(N2CCCC2)CC1

Procedure:
A mixture of 4-pyrrolidin-1-ylpiperidine (0.67 g) and sulfamide (0.46 g) were heated at 115° C. in dry 1,4-dioxane (30 ml) for 16 h. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (containing a little methanol) and H2O. The organic phase was collected and the aqueous layer further extracted with EtOAc(×2). The combined organic phases collected, dried (MgSO4) and the solvent evaporated. The residue was triturated with Et2O and filtered to give the subtitle product as a beige solid. Yield: 0.43 g