Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].B(O)(O)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccncc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and pyridyl-4-boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4 (s, 1H), 8.7 (d, 2H), 8.5 (s, 1H), 8.22 (m, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.9 (m, 1H), 7.85 (d, 2H), 7.7 (t, 1H), 7.5 (m, 2H), 7.45 (d, 1H), 7.0 (d, 1H), 4.3 (t, 2H), 3.6 (m, 4H), 2.9 (t, 2H), 2.55 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH3:14][N:15]([CH3:23])[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20].[H-].[Na+]>>[CH3:14][N:15]([CH3:23])[CH2:16][CH2:17][N:18]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(C)CCNS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
Prepared from 2,4-dinitro-chlorobenzene, N-(2-dimethylamino-ethyl)-methanesulphonamide and sodium hydride as base
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]#[N:10].[NH2:12][NH2:13]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH2:10])[NH:13][N:12]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccn1
Solvent: CCO
Product: Nc1cc(-c2ccccn2)n[nH]1
Yield: 30.2 %

Procedure:
3-(2-Pyridyl)-3-oxopropanenitrile (3.0 g, 0.37 mol) was dissolved in ethanol (22 mL) and treated with hydrazine (1.9 mL, 0.062 mol) at reflux for 24 hours. The reaction mixture was concentrated, diluted with brine and extracted into ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel chromatography eluting with 2-20% methanol in methylene chloride to afford 3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.0 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:29])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:23])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(Cc2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.01 (M+H+); retention time=1.09 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCCF)ccc21
Yield: 16.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(3-fluoro-propoxy)-ethyl]-amide (12 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (55 mg), 2-(3-fluoro-propoxy)-ethylamine (50 mg), HBTU (60 mg), and DIEA (50 uL) in DMF (800 uL). LC/MS: m/z 463.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:17]([CH3:20])(=[O:18])=[O:19])[CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NS(C)(=O)=O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2cccc(N(C)S(C)(=O)=O)c2c1C
Temperature: 80 °C
Yield: 100 %

Procedure:
To a mixture of the product of Example 36, Step 1, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (438 mg, 1.47 mmol, 1 eq) and K2CO3 (430 mg, 3.11 mmol, 2.1 eq) in 4 mL of DMF under nitrogen was added 0.18 mL of iodomethane (2.89 mmol, 2 eq). The reaction mixture was sealed and heated to 80° C. for 18 h. After cooling to room temperature and work up, 4-(methanesulfonyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in pure form without further purification (100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.8 (s, 3 H) 3.0 (s, 3 H) 3.4 (s, 3 H) 4.5 (q, J=7.1 Hz, 2 H) 7.2 (dd, J=7.6, 0.8 Hz, 1 H) 7.4 (m, 1 H) 7.6 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH3:23].O>C(C(C)=O)C>[CH2:22]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:7]1[CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: Clc1ccc(CC2CCCCCN2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCN1CCCCCC1Cc1ccc(Cl)cc1

Procedure:
Boil together (under agitation) 4 g of 2-(4-chlorobenzyl)perhydroazepine, 2.5 g of anhydrous potassium carbonate and 2.9 g of ethyl bromide under reflux for 26 hours in 30 ml of ethylmethylketone. Cool the thus-produced reaction mixture to ambient temperature. Mix the cooled reaction mixture with water and then extract it with diethyl ether. Dry the resulting organic phase over sodium sulfate, remove the ether and distil the residue to obtain 5.12 g (70% of theory) of the title compound with a BP of 112° at 0.005 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9](OC)=[O:10])[CH:7]=1.[CH3:14][NH2:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([NH:15][CH3:14])=[O:10])[CH:7]=1
Reactant: CN
Reactant: COC(=O)Cn1cc(Br)ccc1=O
Solvent: C1CCOC1
Product: CNC(=O)Cn1cc(Br)ccc1=O

Procedure:
A solution of methyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (0.5 g, 1.92 mmol, WO 2009134400) in 2M solution of Methyl amine in THF (5 mL) was stirred at RT for 16 h. The separated solid is collected by filtration and dried under vacuum to afford 2-(5-bromo-2-oxopyridin-1(2H)-yl)-N-methylacetamide as off-white solid, 0.35 g (74%), 1H NMR (400 MHz, DMSO): 8.09 (1H, d, J=4.4 Hz), 7.93 (1H, d, J=2.4 Hz), 7.54 (1H, dd, J=3.0, 9.8 Hz), 6.36 (1H, d, J=9.8 Hz), 4.47 (2H, s), 2.61 (3H, d, J=4.9 Hz). ES-MS: 247.1 (M+2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1Cl)=[CH:6]OCC)[CH3:2].[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[H-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:25]([C:24]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=2[F:22])[CH:6]=1)=[O:21])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O

Procedure:
A solution of 2 g 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester (5.97 mmol) and 0.6 ml of 2,4-difluoroaniline (5.97 mmol) in 15 ml of ethanol was stirred at reflux for 25 hrs. The reaction was monitored by TLC. The ethanol was evaporated and the residual ethanol was distilled from an azeotrope with 20 ml heptane and 20 ml ethyl acetate. The yellow oil was dissolved in 20 ml of THF, reacted with 315 mg of a 50% NaH suspension in oil (6.56 mmol) and stirred at reflux for 20 hrs. The solution was diluted with ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[CH:24]([O:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[CH:24]([O:27][CH2:28][CH2:29][NH:30][C:7]([C:6]1[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])([CH3:26])[CH3:25]
Reactant: CC(C)OCCN
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCOC(C)C

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 2-(isopropoxy)ethylamine in a similar manner as that described for example 108. 1H NMR (CD3CN) δ 8.49 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.6 Hz), 7.82 (1H, d, J=8.6 Hz), 7.54 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8:6, 2.3 Hz), 6.67 (1H, bm), 6.63 (1H, d, J=5.3 Hz), 3.8–3.51 (5H, m), 2.66 (3H, s), 1.15 (6H, d, J=6.1 Hz). Anal. Calcd for C22H22N2O4S: C, 64.37; H, 5.40; N, 6.82; S, 7.81. Found: C, 64.35; H, 5.51; N, 6.76; S, 7.74.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(OCC)(=O)C>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[CH2:8][CH2:7][CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Br[Mg]CCC1OCCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
108 mL of (1,3-dioxan-2-ylethyl) magnesium bromide (0.5M) was added to a solution of 4-bromobenzaldehyde (10 g, 54.0 mmol) in THF (350 mL) at −78° C. under nitrogen and stirred for 2 hours before warming to 0° C. The reaction was quenched with sat NH4Cl soln, diluted with diethyl ether and washed with brine. The crude product was charged (CH2Cl2) to a 40M Biotage silica gel cartridge; Gradient elution 15-100% B over 750 mL (A=Hexanes; B=ethyl acetate) to give Example J1, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (quantitative yield). 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.70-4.66 (m, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.12-4.19 (m, 2H), 3.76 (tt, J=11.9, 2.7 Hz, 2H), 2.87 (d, J=3.7 Hz, 1H), 2.12-2.03 (m, 1H), 1.86-1.87 (m, 2H), 1.74-1.68 (m, 2H), 1.36-1.32 (m, 1H). RT=1.8 minutes (condition 1); LRMS: No parent ion evident.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:18][CH2:19][NH2:20].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:40][C:41]([F:52])([F:51])[C:42]1[C:43]([C:48](O)=[O:49])=[N:44][CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:18][CH2:19][NH:20][C:48]([C:43]1[C:42]([C:41]([F:52])([F:40])[F:51])=[CH:47][CH:46]=[CH:45][N:44]=1)=[O:49]
Reactant: O=C(O)c1ncccc1C(F)(F)F
Reactant: NCCc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)c1ncccc1C(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of 2-chloro-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzeneethanamine hydrochloride (1:1) (i.e. the product of Step C; 300 mg, 1.11 mmol), N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide (297 mg, 1.66 mmol), 1-hydroxybenzotriazole (212 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.9 mL, 5.55 mmol) in dichloromethane (15 mL) was added 3-(trifluoromethyl)pyridine-2-carboxylic acid (198 mg, 1.21 mmol), and the resulting mixture was stirred for 12 h. The reaction mixture was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 50% ethyl acetate in hexanes to afford the title compound (210 mg) as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[N:1]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C1CCN(N2CCNCC2)CC1
Reaction time: 8 h
Yield: 225.5 %

Procedure:
The product of step 4 (1.9 g, 5.79 mmol), N-BOC-4-piperidone (5.73 g, 28.8 mmol), NaBH(OAc)3 (6.1 g, 28.8 mmol) and 2M AcOH (5.76 ml, 11.52 mmol) were combined in CH2Cl2 (150 ml) and the mixture was stirred overnight. After the solvent was removed, NaOH (3N) was added and extractive work up with EtOAc followed by silica gel chromatography afforded pure piperazino-piperidine (2.21 g, 75% yield, Rf=0.18, hexanes/EtOAc, 1:1) as a syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH:22][C:33]([C:29]2[CH:28]=[C:27]3[C:32]([C:24]([Cl:23])=[CH:25][NH:26]3)=[CH:31][CH:30]=2)=[O:34])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@@H](N)COCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CCCC[C@H](COCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using coupling method A, 4-[(R)-2-amino-2-(butyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (195 mg, 0.62 mmol) and 3-chloroindole-6-carboxylic acid (133 mg, 0.68 mmol) afforded, after purification (SiO2: 40% EtOAc in hexane), 90 mg (29%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reaction time: 19 h
Yield: 90.8 %

Procedure:
Combine a slurry of 0.176 kg of 10% Pd-C (50% water wet) and 1.7 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide in 17.5 L of DMF with hydrogen (50 psi, 345 kPa). After 19 h, filter the reaction mixture, add a portion of the DMF solution (5 L) to water (10 L), and stir the slurry for 2 h-repeat twice to work up the entire reaction volume. Filter the slurries together, and wash the resulting filter cake with water (3×7 L). Dry the filter cake to afford 1.42 kg of biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide.
Reaction SMILES: [C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-]>>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: [Ca+2]
Agent: [Cl-]
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 48 %

Procedure:
The hydrolysis of 1.60 g (5.12 mmol) of ethyl (RS)-α-[(tert-butylsulfonyl)methyl]hydrocinnamate was carried out in a manner analogous to Example 1 in the presence of 25 ml of aqueous 5 mM calcium chloride solution and 100 mg of Alcalase 2.0 T (NOVO, 2880 Bagsvaerd, Denmark). After a consumption of 2.47 ml of 1N sodium hydroxide solution (after 21.3 hours), the reaction mixture was worked-up analogously to Example 1, whereby there were obtained 700 mg (2.46 mmol, 48%, 96% of theory) of (S)-α-[(tert-butylsulfonyl)methyl]hydrocinnamic acid, which had not only an enantiomeric excess, but also a gas chromatographical (GC) purity of, in each case, >99%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12]Br.C(#N)C>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ClCCBr
Reactant: c1ccc2c(c1)CCN2
Solvent: CC#N
Solvent: ClCCl
Product: ClCCN1CCc2ccccc21

Procedure:
A microwave vial was charged with indoline (0.5 g, 4.19 mmol), 2-chloro-1-bromoethane (0.502 ml, 6.25 mmol), TEA (0.7 ml, 6.25 mmol) and acetonitrile (10 ml). The vial was irradiated with microwaves for 1 hour at 80° C. The mixture was diluted with DCM and washed with water (1×10 ml). The organic layer was dried and concentrated and the residue was purified by flash column chromatography (silica, Hexane/EtOAc 95:5 to 0:1). The product was isolated as a violet solid (400 mg; 52%).
Reaction SMILES: C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:16]=[C:15]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH:33]([CH3:34])[C:13]=1[C:14]=23>>[CH3:34][CH:33]1[C:13]2=[C:14]3[C:18](=[CH:19][CH:20]=[C:12]2[OH:11])[N:17]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:16]=[C:15]3[CH2:30][CH2:31][NH:32]1
Reactant: CC1c2c(O)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NCCc2cn(S(=O)(=O)c3ccccc3)c3ccc(O)c1c23
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50/50 mixture of DCM/TFA (1 mL) was added to tert-butyl 7-hydroxy-6-methyl-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 15 (16 mg, 0.036 mmol) and the mixture was stirred at room temperature for one hour. The solvent was evaporated at reduced pressure and the crude product was purified by preparative HPLC (Xterra C18, 10 mM NH4CO3 (pH 10)-CH3CN) to give 6.9 mg of the title compound. MS m/z 343 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21]C(OC(C)C)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][Cl:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][CH:13]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:13]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCc1c[nH]c2ccc(Cl)cc12)Cc1ccccc1
Reactant: Fc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)Cc1ccccc1
Temperature: 165 °C

Procedure:
A mixture of N-benzyl-N-methyl-2-(5-chloro-3-1H-indolyl)ethylamine (16 g, 0.054 mol), 4-fluoro-iodobenzene (14.3 g, 0.064 mol), K2CO3 (11.1 g, 0.080 mol) and 1-methyl-2-pyrrolidinone (200 mL) was heated at 165° C. for 8 h. After cooling to room temperature water (250 mL) was added and the thus formed mixture was extracted with diethyl ether (2×300 mL). The combined organic phases were washed with brine (3×500 mL) and dried (Na2SO4). Evaporation of the solvent afforded an oil that was purified by column chromatography (eluted with ethyl acetate/heptane 1:3) affording pure title compound as an oil: 13.7 g (26%) 1H NMR (CDCl3) δ 2.35 (s, 3 H), 2.70-2.80 (m, 2 H), 2.90-3.00 (m, 2 H), 3.60 (s, 2 H), 7.05-7.40 (m, 12 H), 7.55 (broad s, 1 H).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][O:29][CH3:30])[CH:22]=1)[C:3]([NH:5][C:6]1([O:19][CH3:20])[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([OH:17])=[O:16])=[O:4].[Na].Cl[CH2:33][O:34][C:35](=[O:48])[C@H:36]([CH:45]([CH3:47])[CH3:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][O:29][CH3:30])[CH:22]=1)[C:3]([NH:5][C:6]1([O:19][CH3:20])[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([O:17][CH2:33][O:34][C:35](=[O:48])[CH:36]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH:45]([CH3:47])[CH3:46])=[O:16])=[O:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: COCc1cc(C(N)C(=O)NC2(OC)C(=O)N3C(C(=O)O)=C(C)CSC32)ccc1O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cc(C(N)C(=O)NC2(OC)C(=O)N3C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(C)CSC32)ccc1O
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 7-[[amino[4-hydroxy-3-(methoxymethyl)phenyl]acetyl]amino]-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to give 7-[[amino[4-hydroxy-3-(methoxymethyl)phenyl]acetyl]amino]-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.