Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:46])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:13]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[O:14])[C:8](=[O:25])[N:7]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])=[O:35])=[C:29]([O:44]C)[CH:28]=1.O>ClCCl>[CH3:46][C:6]1([CH3:5])[C:10](=[O:11])[N:9]([C@@H:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:13]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][OH:19])=[O:14])[C:8](=[O:25])[N:7]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])=[O:35])=[C:29]([OH:44])[CH:28]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CCO)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CCO)C(=O)C2(C)C)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
488 μL of boron tribromide were added under argon to a solution of 220 mg (0.39 mmol) of the compound of Example 3 in 40 mL of absolute dichloromethane at −78° C. and the reaction mixture was allowed to warm to 0° C. with ice cooling. After 30 minutes at 0° C., water was cautiously added. The phases were separated, and the organic phase was washed four times with water and dried over sodium sulfate. After filtration, removal of the solvent in vacuo, chromatographic purification by preparative HPLC and freeze drying of the product fractions, 81 mg (37%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1)(=[O:33])=[O:32]
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)OC(C)(C)c2cc(NS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
To a stirred solution of 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.15 g, 0.73 mmol) in methylene chloride (5 mL) at 0° C. was added triethylamine (0.15 mL, 1.07 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.27 g, 1.10 mmol) was added. The solution was stirred for 5 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 30% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as an off-white solid (0.015 g, 5%). 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 8.02 (dd, J=7.9, 1.4 Hz, 1H), 7.93 (dd, J=8.1, 1.4 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.03 (m, 3H), 3.20 (s, 3H), 1.48 (s, 6H). MS (ESI) m/z 415/417/419 ([M+H]+); MS (ESI) m/z 413/415/417 ([M−H]−).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[N:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.C1COCC1>[ClH:24].[ClH:24].[NH2:21][C:19]1[C:18]([C:22]#[N:23])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C#N)c(N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC2CCNCC2)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(4-amino-5-cyano-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.02 g, 9.49 mmol) in dioxane (10 mL) and THF (10 mL) was added 4 M HCl in dioxane (50 mL) and the reaction mixture stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 219.1 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:26][S:27]SC>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:27][CH3:26])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSSC
Reactant: Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To a chilled solution of 1-benzenesulfonyl-5-bromo-2-methyl-1H-indole (350 mg, 0.99 mmol) in 4 mL of THF was added 440 μL (1.10 mmol) of n-BuLi (2.5 M solution in hexanes), followed by dimethyl disulfide (100 μL, 1.11 mmol). The mixture was stirred as it warmed to room temperature and was then quenched with ammonium chloride and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes (1:99, then 2:98) to afford 156 mg (44.3% yield) of 1-benzenesulfonyl-2-methyl-5-methylsulfanyl-1H-indole as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: NCCCO
Reactant: COc1ccc(Br)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(Br)c(CNCCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-methoxybenzaldehyde (1 eq) in dichloroethane was added 3-aminopropanol (1.5 eq) followed by NaBH(OAc)3 (2 eq) and acetic acid (4 eq) and the resulting mixture was stirred at RT under nitrogen for 8 h. The reaction mixture was quenched by careful addition of 2M Na2CO3 solution and stirred 1 h. The mixture was concentrated in vacuo and poured into diethyl ether. The phases were separated and the organic phase washed with 1N HCl solution. The aqueous phase was then washed with diethyl ether and subsequently basified with 1N NaOH solution. The aqueous phase was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 3-(((2-bromo-5-methoxyphenyl)methyl) amino)propan-1-ol as a clear oil. EI-MS m/z 274, 276 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)[CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[C:12]=2[C:34]([O:36]CC)=[O:35])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:39]>>[ClH:39].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)[CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[C:12]=2[C:34]([OH:36])=[O:35])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NCC3CC3)ccc2n1Cc1cccc(OC)c1
Agent: Cl
Product: COc1cccc(Cn2c(C(=O)O)c(-c3ccc(C(C)(C)C)cc3)c3cc(NCC4CC4)ccc32)c1
Yield: 59 %

Procedure:
Ethyl 3(4-tert-butylphenyl)-5-[(cyclopropylmethyl)amino]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 165, 420 mg, 0.84 mmol) was reacted using the method described for Example 237. After hydrolysis the solution was adjusted to pH=1 using 1 M hydrochloric acid. The resulting precipitate was collected by filtration, using ethyl ether to wash, to afford 250 mg, (59%) of product. The product had: 1H NMR (300 MHz, CD3OD) δ 7.71 (d, 1 H), 7.39-7.59 (m, 6 H), 7.16 (dd, 1 H), 6.72-6.80 (m, 1 H), 6.61-6.69 (m, 2 H), 5.84 (s, 2 H), 4.36 (s, 2 H), 3.71 (s, 3 H), 2.68-2.80 (m, 1 H), 1.41 (s, 9 H), 1.15-1.25 (m, 1 H), 0.80-0.96 (m, 4 H); mass spectroscopy gave MH+−HCl=483.3 (calcd exact mass for C31H34N2O3=482.26).
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BrH:12].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:12][CH2:2][C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([NH2:11])=[O:10])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(N)=O)cs1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1csc(C(=O)CBr)c1

Procedure:
A solution of 5-acetylthiophene-3-carboxamide (0.5 g) in chloroform at 50° was treated with hydrogen bromide in acetic acid (4 drops) and then bromine (0.15 ml) in chloroform (10 ml) dropwise over 30 min. The resulting pale yellow solution was washed with water (2×100 ml), dried and evaporated to small volume to deposit the title compound as a white solid (0.55 g) which recrystallised from water, m.p. 150°-157° (d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c(F)c1
Product: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c(F)c1

Procedure:
2-(4-{4-[8-(2-Fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2-fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.179 g, 0.429 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.066 mL, 0.643 mmol) in a manner analogous to Example 313 to give product (0.105 g, 49%). MP=192-195° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.61 (s, 1H), 8.79 (d, 1H), 7.80 (m, 1H), 7.58 (m, 3H), 7.15 (m, 3H), 6.98 (m, 2H), 3.85 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.92 (m, 2H), 2.85 (s, 3H), 2.40 (m, 1H), 2.10 (m, 2H), 1.65 (m, 4H). MS=503 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(N)c1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-methoxyaniline (61.6 mg, 0.50 mmol) as described in General Procedure X to afford Iag (26 mg, 37.7%) as an ivory colored solid, tlc Rf=0.6 (5% MeOH/CH2Cl2-0.2% Et3N), m/z obs=404 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[C:27](C2C=C3C(I)=CNC3=NC=2)[CH:26]=[CH:25][C:24]=1[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]3[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:14])=[O:13])[C:5]3=[N:6][CH:7]=2)[CH:26]=[CH:25][C:24]=1[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(I)c4c3)cc2F)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 48.26 %

Procedure:
Using similar reaction conditions as described in, step ii of Intermediate 1, tert-butyl 4-(2-fluoro-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (400 mg, 0.767 mmol) was tosylated with p-toluene sulfonylchloride (220 mg, 1.151 mmol) and DMAP (282 mg, 2.303 mmol) in DCM (20 mL) to afford 250 mg (48.26% yield) of the titled compound after purification with (60/120 silica gel) column chromatography using 1% methanol in DCM as eluent. MS: m/z=676.3 (M+1). 1H NMR (CDCl3, 300 MHz): δ 8.619-8.611 (d, 1H), 8.12-8.09 (d, 2H), 7.89 (s, 1H), 7.767-7.760 (d, 1H), 7.31-7.23 (m, 5H), 4.26 (s, 2H), 3.08-3.00 (m, 1H), 2.95-2.75 (m, 2H), 2.38 (s, 3H), 1.86-1.64 (m, 4H), 1.489 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: N#CCC#N
Product: COc1cc(Cl)ccc1C=C(C#N)C#N

Procedure:
By the method used for Intermediate 3,4-chloro-2-methoxybenzaldehyde from Step A was reacted with malononitrile to afford the title compound as a yellow solid. LC-MS 219 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]=[C:11]([C:13]3[CH:27]=[C:26]([CH3:28])[C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([CH3:29])[CH:14]=3)[O:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([C:2]1[C:3]2[N:12]=[C:11]([C:13]3[CH:27]=[C:26]([CH3:28])[C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([CH3:29])[CH:14]=3)[O:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CSc1nc(Cl)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Reactant: CC(C)C[Mg]Br
Product: CSc1nc(CC(C)C)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Yield: 20 %

Procedure:
Analogously to example 1 (g), the reaction of 1.50 g of tert-butyl [4-(7-chloro-5-methylsulfanyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with isobutylmagnesium bromide gave 0.31 g (20%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.O.[CH:13](O)=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:13]=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: COc1cccc(CCN)c1
Solvent: O
Product: COc1cccc(CCNC=O)c1
Yield: 73 %

Procedure:
A solution of 2-(3-methoxy-phenyl)-ethylamine (50.0 g, 0.33 mol) in formic acid (60 mL) was refluxed overnight. Water (250 mL) was added and the emulsion extracted with ethyl acetate (2×150 mL). The organic layer was separated, dried (Na2SO4) and concentrated to give N-[2-(3-methoxy-phenyl)-ethyl]-formamide (43.1 g, 73%). MS: 180.1 (M+1+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 100.0 grams (0.64 mole) of ethyl piperidin-4-ylcarboxylate and 94 mL (0.67 mole) of triethylamine in 1400 mL of diethyl ether was cooled to 15° C., and a solution of 86 mL (0.68 mole) of chlorotrimethylsilane in 100 mL of diethyl ether was added dropwise during a 30 minute period. Upon completion of the addition, the thick reaction mixture was stirred vigorously for one hour while warming to ambient temperature. The reaction mixture was then filtered, and the collected solid was washed with diethyl ether. The combined wash and filtrate were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 115.0 grams (79% yield) of ethyl N-(trimethylsilyl)piperidin-4-ylcarboxylate, bp 75° C./0.1 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([Cl:24])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=C1c2cccc(Cl)c2C(=O)N1C1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1c2cccc(Cl)c2C(=O)N1C1(C(=O)Cl)CCCCC1
Reaction time: 2 h

Procedure:
In a 12 liter flask is placed 1.5 kg. of the 1-(3-chlorophthalimido)cyclohexanecarboxylic acid and 7500 ml. benzene. The mixture is stirred and heated to boiling, and then 696 grams thionyl chloride added dropwise. After the addition, heating is continued for 2 hours. The volume of the solution is reduced by one-half, the solution filtered, and the remaining solvent removed under reduced pressure. The acid chloride is used for the preparation of the carboxamides without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.Cl>[CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][OH:23])[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO)Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4, 3.0 g, 6.0 mmol) in dioxane (20 mL), hydrochloric acid in dioxane (20 mL) was added at room temperature. The mixture was stirred for 16 h. After completion, the solvent was removed. The residue was diluted with aqueous sodium bicarbonate and extracted with 5% methanol/dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to get N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1, 6-dihydropyridine-2-carboxamide (5) as brown liquid. Yield: 2.2 g, 95%; MS (ESI) m/z 381.22 [M−1]−.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH:5]([C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[S:28][CH:29]=1)[N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:14]([O:23][CH3:24])=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:8][CH2:7]1.[OH-].[Na+].CO>C1COCC1>[OH:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[S:28][CH:29]=[C:25]([CH:5]([N:6]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]4[C:14]([O:23][CH3:24])=[CH:15][CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:8][CH2:7]3)[CH2:4][C:3]([OH:37])=[O:2])[N:26]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)CC(c1csc(N2CCC(O)CC2)n1)N1CCCN(c2c(OC)ccc3cccnc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2csc(N3CCC(O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from step 1 (660 mg, 1.26 mmol) was dissolved in THF (4.20 mL) and 1 N aq. NaOH (2.52 mL, 2.52 mmol) was added, followed by MeOH (2.10 mL). The reaction was stirred at room temp for 3 h, then concentrated. The product was taken up in CH2Cl2 and water, then acidified to pH 4 with AcOH. NH4OH was added to bring the pH to 9, then the aqueous was extracted with CH2Cl2 (3×50 mL). The combined organic was dried over MgSO4, filtered, and concentrated to give the product, which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:41][CH2:42][N:43]([CH2:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[CH2:44][CH2:45]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccccc23)CC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(N2CCN(C[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1H-3-indolyl)-cyclohexanecarboxylic acid (1.60 g, 6.57 mmol) and methylene chloride (30 mL) is treated with triethylamine (1.53 mL, 10.97 mmol) and the resulting solution is cooled to 0° C. Isobutyl chloroformate (0.93 mL, 7.15 mmol) is added and the reaction is stirred at 0° C. for 10 minutes. A solution of 1-(2-pyridinyl)piperazine (1.18 g, 7.23 mmol) in methylene chloride is added and the reaction is then stirred at ambient temperature for 18 hours. A saturated solution of sodium bicarbonate (20 mL) is added and the organic phase is separated. The aqueous phase is extracted with two 40 mL portions of methylene chloride and the combined organic extracts are dried with sodium sulfate, and evaporated. The residue is chromatographed on silica gel (2% methanol in chloroform) and 2 main fractions are isolated. The first fraction consisted of trans 1-({4-[1H-3-indolyl]cyclohexyl}carboxyl)-4-(2-pyridinyl)piperazine and the second fraction consisted of the corresponding cis isomer. The resulting trans amide is reduced by the method described in Example 1 to give trans 3-[4-[4-(2-pyridinyl)-1-piperazinylmethyl]cyclohexyl]-1H-indole (Example 15); m/e 374.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][N:18](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:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1)#[N:18]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
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]
Product: COC(=O)C1=Cc2cc(C#N)ccc2OCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (1416 mg, 5.00 mmol), zinc cyanide (352 mg, 3.00 mmol), tetrakis(triphenylphosphine)palladium (347 mg, 0.30 mmol) and DMF(10 ml) was stirred at 80° C. for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. Insoluble materials were filtered off, which were washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate to give methyl 7-cyano-2,3-dihydro-1-benzoxepine-4-carboxylate (800 mg, 3.49 mmol, 70%).