Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH:16]([CH3:19])[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:19])[C:17]#[N:18])[CH:10]=2)[O:3]1
Reactant: CC(Cl)C#N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, Cat. No. 525057)(0.22 g, 1.1 mmol), 2-chloropropanenitrile (Aldrich, Cat. No. 192406) (0.12 g, 1.4 mmol), and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (4.0 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=248.1.
Reaction SMILES: COC([CH2:5][N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:7]1=[O:20])=O.[CH2:21]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][C:22]1=O.[C:32]([OH:35])(=[O:34])[CH3:33].C([BH3-])#N>C1COCC1.ClCCCl>[CH3:33][C:32]([O:35][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][C:16]([CH:22]3[CH2:23][CH2:24][CH:25]4[CH:30]([CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21]3)=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:7]1=[O:20])=[O:34]
Reactant: O=C1CCC2CCCCC2C1
Reactant: COC(=O)CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: CC(=O)O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)OCN1C(=O)C2(CCNCC2)c2cc(C3CCC4CCCCC4C3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Methoxycarbonylmethyl)-spiro[indoline-3,4′-piperidin]-2-one (0.013 g, 0.049 mmol) was dissolved in dry THF (1.0 mL) and dry 1,2-dichloroethane (0.3 mL). Octahydro-naphthalen-2-one (0.008 g, 0.054 mmol), glacial acetic acid (0.003 g, 0.049 mmol), MP-cyanoborohydride (Polymer support from Argonaut) (0.043 g, 0.099 mmol) were added and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was then filtered, the resin washed with dichloromethane and the solvent evaporated in vacuo to yield the crude compound. The crude compound was purified via flash chromatography (5% methanol/dichloromethane) to yield the title compound as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 860 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 5 ml of DCM, 0.8 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 320 mg
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CN([CH:30]=[O:31])C>N1C=CC=CC=1>[CH2:25]([O:24][C:22]([CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[C:30](=[O:31])[C@H:22]([O:24][CH2:25][C:4]1[CH:5]=[CH:6][CH:17]=[CH:16][CH:15]=1)[CH3:14])=[O:23])[CH3:26]
Reactant: CN(C)C=O
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)[C@@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
16.6 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and then 10 g of ethyl indoline-2-carboxylate are added to a solution of 12.6 g of o-benzyl-D-lactic acid in 30 ml of DMF and 10.6 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 hours. The reaction medium is concentrated under reduced pressure to ⅔ of the volume of the reaction medium. Ethyl acetate and water are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica cartridge: eluent: gradient: heptane/ethyl acetate from 100/0 to 80/20, so as to give 7.24 g of 1-((R)-2-benzyloxypropionyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester: diastereoisomer A, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:17])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(1-cyano-1-methylethyl)benzoic acid (9.87 g, 52.2 mmol) in toluene (150 mL) was added thionyl chloride (25.3 g, 213 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a colorless oil. To a solution of 4-methyl-3-nitroaniline (7.63 g, 50.2 mmol) in pyridine (150 mL) were added N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and 3-(1-cyano-1-methylethyl)benzoyl chloride, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL), and dried over anhydrous magnesium sulfate. After filtration through a silica gel pad, the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-(4-methyl-3-nitrophenyl)benzamide as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13]1=[O:18]
Reactant: CN1CCNCC1=O
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][I:5].I.CN(CCI)P(Cl)(Cl)=O.[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])(N(C)CCBr)=[O:25])[CH2:19][O:18]1>>[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])([N:2]([CH3:1])[CH2:3][CH2:4][I:5])=[O:25])[CH2:19][O:18]1
Reactant: CNCCI
Reactant: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Agent: CN(CCI)P(=O)(Cl)Cl
Agent: I
Product: CN(CCI)P(=O)(Cl)CCC1COC(C)(C)O1
Yield: 61 %

Procedure:
This compound was prepared using N-methyl-N-2-iodoethylamine.HI via N-methyl-N-(2-iodoethyl)phosphoramidic dichloride, as described for 16a (10 mmol scale). The crude product was purified by chromatography (1:4 EtOAc:hexanes) which afforded 16c as a pale yellow oil (2.50 g, 61%): Rf 0.67 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.27(m, 3H), 4.10(t, 1H, J=6.52 Hz), 3.59(t, 1H, J=7.38 Hz), 3.44(m, 2H), 3.26(t, 2H, J=7.56 Hz), 2.78(d, 3H, J=12.89 Hz), 2.00(dt, 2H, J=6.02 Hz), 1.38(d, 6H, J=15.48 Hz)ppm; 31P NMR (CDCl3) -8.46, -8.69 ppm (1:1 ratio of diastereomers).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[N:27]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)N3CCOCC3)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a 15 mL RB flask was added N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.065 g, 0.222 mmol), 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.055 g, 0.266 mmol), and DMF (3.0 mL). The mixture was cooled to 0° C. under N2. sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.888 mL, 0.888 mmol) was added to the solution in one portion. The now dark brown mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (42.0 mg). MS (ESI pos. ion) m/z: 478.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.15 (br. s., 4H) 3.61 (br. s., 4H) 7.03 (dd, J=7.53, 4.60 Hz, 1H) 7.79 (br. s., 1H) 7.91 (br. s., 1H) 8.38 (d, J=3.36 Hz, 1H) 8.51 (s, 1H) 8.82 (d, J=5.41 Hz, 2H) 9.78 (s, 1H) 12.26 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c1CCC2=O
Reaction time: 8 h

Procedure:
To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml of N-ethyldiisopropylamine in 30 m of dichloromethane, 2.3 ml of chloromethyl methyl ether was added dropwise while stirring under ice cooling. An ice bath was removed and the mixture was continuously stirred overnight. The reaction solution was diluted with diethyl ether, washed with water, an aqueous 10% citric acid solution and an aqueous 5% sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4.23 g of the desired compound as a pale orange crystal having a melting point of 51 to 54° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[S:11]1(=O)(=O)[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.[NH3:20]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:12]3[S:11][CH2:16][CH2:15][CH2:14][C:13]=3[NH:20][C:13]3[CH2:14][CH2:15][CH2:16][S:11][C:12]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1CCCS(=O)(=O)C1
Reactant: N
Solvent: CCO
Product: Fc1ccc(C2C3=C(CCCS3)NC3=C2SCCC3)cc1Br

Procedure:
3-Bromo-4-fluorobenzaldehyde (202 mg, 1.0 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (305 mg, 2.06 mmol) and 2.0 M NH3 in ethanol (0.70 mL, 1.4 mmol) were heated in ethanol (3 mL) to 80° C. for 5 days in a sealed tube, cooled, the solid precipitate collected and washed with ethanol. The solid in toluene (10 mL) was then heated to reflux overnight, cooled, the solid collected, washed with ethanol and dried to provide 129 mg of the title compound as a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].N([C@@H]1CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OCC1=O)=[N+]=[N-]>>[N:1]([C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][C@@H:5]1[OH:20])=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Agent: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])C(=O)CO1
Product: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@@H](O)CO1
Yield: 74 %

Procedure:
Following the procedure for Intermediate 57 starting from (4R,7S)-4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-one gave (3R,4R,7S)-4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol as a dark orange oil (850 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.68-5.60 (m, 1H), 4.24-4.14 (m, 3H), 4.01 (s, 3H), 3.72-3.58 (m, 1H), 2.45-2.31 (m, 1H), 2.30-2.09 (m, 2H), 2.01-1.81 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:11](OCC)=[O:12].[H-].[Na+].[H][H].[BH4-].[Na+]>C(O)(=O)C.O.CCOCC>[Cl:1][C:2]1[CH:3]([CH2:11][OH:12])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC=O
Reactant: ClC1=Cc2ccccc2C1
Reactant: [H][H]
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: OCC1C(Cl)=Cc2ccccc21

Procedure:
A flask is charged with 75 gr (0.5 mol) 2-chloroindene, 50 ml (0.6 mol) ethyl formate, 400 ml dry ether and 23 gr (0.6 mol) sodium hydride (55-60% dispersion in oil). The mixture is heated to reflux to start the reaction, as indicated by a vigorous hydrogen evolution. The flask is cooled in an ice water bath, until hydrogen evolution subsides, then refluxed again for an additional ten minutes. Excess sodium hydride is carefully decomposed with water, and more water is added to form two layers. The aldehyde dissolves in the aqueous basic solution which is extracted several times with ether. To the aqueous solution are added 19 gr (0.5 mol) sodium borohydride. With vigorous stirring and cooling in an ice water bath, glacial acetic acid is added dropwise at a rate of a drop per second, until the mixture becomes acidic. The alcohol is extracted with ether and the organic solution dried and evaporated. The crude alcohol (75 gr, 83%) is recrystallized from carbon tetrachloride, to give white crystals, m.p. 104°-105° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:9][CH:10]=1)[CH3:3]
Reactant: O=C(O)c1ccncc1F
Reactant: CC(C)Oc1ccc(CN)cc1
Product: CC(C)Oc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 1-(4-isopropoxyphenyl)-methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.21 (d, 2H, J=8.0 Hz), 4.49 (s, 2H), 2.82-2.89 (m, 1H), 1.19 (d, 6H, J=4.5 Hz). [M+H] calc'd for C16H18N2O3, 287; found 287.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].IC.[C:18](=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:18][O:14][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:6]=1)=[O:15]
Reactant: COCCOc1nc(C(=O)O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COCCOc1nc(C(=O)OC)ccc1Br
Yield: 66.7 %

Procedure:
A solution of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (2.48 g, 9 mmol), iodomethane (2.55 g, 18 mmol) and sodium carbonate (0.106 g, 9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed three times with brine, dried (sodium sulfate) and evaporated. The residue was purified by column chromatography (silica gel, 50 g, 30% ethyl acetate in petroleum ether) to yield the title compound (1.7 g, 6 mmol, 65%) as yellow solid; MS (EI): m/e 290.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:44]([N:41]([CH2:42][CH3:43])[C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:45]
Reactant: CCN(CC)c1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-diethylaminophenyl borate (123 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate/THF (1:1), washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-(4-diethylaminophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 54) (198 mg).
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1O>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[O:16][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:14][CH2:13]1)=[O:17]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1OC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 96 h

Procedure:
To a stirred solution of N-Cbz-1-aminocyclopropane carboxylic acid in dry (CH2)2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethylcyclopentanol dissolved in CH2Cl2. After stirring for 4 days, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.S(Cl)([Cl:11])=O>C(#N)C>[ClH:11].[Cl:11][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: OCc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Cl
Product: ClCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxymethylpyridine (20) (54.4 g, 0.50 mol) was dissolved in acetonitrile 202 ml. The solution was added dropwise to a mixture of thionyl chloride (65.3 g, 0.55 mol) and acetonitrile (109 ml) under 50° C. The mixture was stirred at the same temperature for 1 hour, then cooled to room temperature to yield a slurry (quantitative) of the objective (21).