Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C1(C)C=CC=CC=1.[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([O:15][S:2](=[O:3])(=[O:4])[NH2:5])=[CH:17][CH:18]=1)=[O:21]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OS(N)(=O)=O)cc1

Procedure:
Chlorosulfonylisocyanate (8.8 ml, 0.1 mole) was added to 200 ml toluene. Solid methyl 4-hydroxybenzoate (15.2 g, 0.1 mole) was added to the stirred solution. The mixture was heated at reflux for 1.5 hr then cooled and treated with about 8 ml water and some tetrahydrofuran. Solvents were then removed by evaporation. The residue was triturated with ethyl acetate-isopropyl ether. The insoluble solid was removed by filtration. The filtrate was concentrated and then triturated in isopropyl ether. The solid was collected and weighed 8.6 g. Recrystallization from acetone-isopropyl ether gave a white solid which was dried under vacuum overnight at room temperature to 3.9 g, mp 116°-118° C.
Reaction SMILES: CN1CCOCC1.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=O)=[O:16])[CH2:10][CH2:9]1.[NH2:23][C@@H:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[O:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([NH:23][C@@H:24]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:21])=[O:16])[CH2:12][CH2:13]1
Reactant: N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
N-Methylmorpholine (1.09 g, 10.8 mmol) was added to a mixture of (S)-2-(2-morpholinoacetamido)propanoic acid (0.58 g, 2.7 mmol), (S)-benzyl 2-amino-4-phenylbutanoate (TFA salt, 1.03 g, 2.7 mmol) and HATU (1.13 g, 2.97 mmol) in dichloromethane (50 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (50 mL) was added and the resulting mixture was extracted with dichloromethane (50 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 10:1) to afford (S)-benzyl 2-((S)-2-(2-morpholinoacetamido)propanamido)-4-phenylbutanoate (0.9 g, 71% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[NH:45][CH:46]=[C:47]([CH3:49])[N:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[NH:45][CH:46]=[C:47]([CH3:49])[N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Cc1c[nH]c(Br)n1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3nc(C)c[nH]3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 2-bromo-4-methyl-1H-imidazole.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1.O>C1COCC1>[C:31](/[C:30](=[C:20]1/[C:21]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=2[O:23][CH2:24][C:18]2[CH:17]=[C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:35]=[CH:34][C:19]/1=2)/[CH3:33])#[N:32]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCCC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
[step 1] Ethyl 3-oxohexanoate (883 mg, 5.58 mmol) was dissolved in THF (9 mL), sodium hydride (60% w/w, 190 mg, 4.75 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the mixture was added dropwise a solution (9 mL) of (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (1.0 g, 2.79 mmol) obtained in Reference Example 1 in tetrahydrofuran, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 v/v) to give (E)-ethyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-3-oxohexanoate (1.19 g, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10]
Reactant: CCS(=O)(=O)c1ccc(NC(C)=O)cc1C#N
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(NC(C)=O)cc1CN
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To 5C (423 mg, 1.65 mmol) in MeOH (17 mL), Raney Ni (cat) was added. The mixture was stirred under hydrogen (60 psi) for 8 h, then filtered and concentrated to provide 5D (397 mg, 92%). LC-MS: 253.23 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][NH2:37])[CH3:30]>O1CCCC1.ClCCl>[CH2:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[CH2:36][NH:37][C:4](=[O:6])[C:3]1[C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=[C:10]([Br:11])[C:2]=1[NH2:1])[CH3:30]
Reactant: COc1cc(Br)c(N)c(C(=O)O)c1OC
Reactant: CCN1CCC[C@H]1CN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCC[C@H]1CNC(=O)c1c(N)c(Br)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 2-amino-3-bromo-5,6-dimethoxybenzoic acid (0.96 g, 3 mmol) and triethylamine (0.58 ml, 4.2 mmol) in 15 ml tetrahydrofuran/ /dichloromethane (1:1) was added ethyl chloroformate (0.32 ml, 3.4 mmol) at -20° C. After stirring for 45 min. at -20° C. a solution of (2S)-(-)-1-ethyl-2-aminomethylpyrrolidine in 10 ml dichloromethane was added at -20° C. After stirring for 3 h at room temperature the mixture was washed with water and extracted with 0.5M HCl. The aqueous phase was made alkaline and extracted twice with dichloromethane. Drying (Na2SO4) and evaporation gave 0.45 g crude material which was purified by chromatography on a C18 reversed phase column with H2O/MeOH/NH3 40:60:0.3 as eluent to give 0.25 g (22%) pure product as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24](O)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:4])=[O:3].Cl.[C:28]([S:47][CH2:48][CH2:49][NH2:50])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([NH:50][CH2:49][CH2:48][S:47][C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of 7-{[2-(methylsulfonyl)phenylsulfonyl]amino}-1H-indole-2-carboxylic acid (1.00 g), 2-(tritylthio)ethylamine hydrochloride (0.92 g), 1H-1,2,3-benzotriazol-1-ol (0.41 g), triethylamine (0.42 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.58 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.78 g, quantitative) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 91-93° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4].C(O)(=O)C>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2C(=O)O)N1
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness and refluxed for 2 hours with 1.1 g of tin (11) chloride in 20 mL of ethanol. The mixture was filtered through Celite, concentrated and chromatographed on silica gel in ethyl acetate:hexane;acetic acid to give 0.65 g (37% yield) of 4-carboxy-2-oxindole as a while solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH2:40][CH2:39][O:38][CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Reactant: COCCBr
Product: COCCN1C[C@H](O)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 182) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[NH4+].[Cl-].Cl>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:17]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCCC1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCC2)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
4-Bromo-3-fluoro-benzoic acid (3.00 g, 13.7 mmol) was dissolved in tetrahydrofuran (60 mL) and the solution was cooled to −78° C. n-Butyllithium (18.8 mL of 1.6 M in hexanes, 30 mmol) was added dropwise over 20 min while maintaining the internal temperature under −70° C. The reaction mixture was allowed to stir for 30 min at −78° C. and then cyclopentanone (1.21 mL, 13.7 mmol) was added in a dropwise while maintaining the internal temperature below −70° C. The mixture was stirred at −78° C. for 30 min the allowed to warm to room temperature. The reaction mixture was diluted with saturated NH4Cl (50 mL) and 1 M HCl (25 mL) and extracted with dichloromethane (3×50 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography (0-5% methanol/dichloromethane) provided 3-fluoro-4-(1-hydroxycyclopentyl)benzoic acid (400 mg, 13%) as a white solid. ESI-MS m/z calc. 224.1. Found 225.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.80-7.70 (m, 2H), 7.60-7.51 (m, 1H), 5.13 (s, 1H), 2.08-1.95 (m, 2H), 1.95-1.81 (m, 4H), 1.81-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Br:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Br:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-bromo-1H-indazole-3-carbaldehyde (0.0587 g, 0.261 mmol) synthesized in Example B10, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-bromo-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.110 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.Cl.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:14][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Cl)[nH]c2ccccc12
Yield: 47.7 %

Procedure:
A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mole) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mole) to afford a clear solution within 15 minutes. After 2 h at room temperature this was treated with 1M HCl/ether (34 ml, 0.034 mole) and allowed to stir for a further 1h, then treated with excess 10% Na2CO3 solution and the chloroform layer separated, dried (Na2SO4) and concentrated in vacuo. The residual yellow solid was recrystallised from chloroform/60-80 petrol to afford the title compound (D11a) as a beige solid (3.4 g, 48%).
Reaction SMILES: [CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+]>CN(C=O)C.O>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:25][C:26]([OH:28])=[O:27])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 55 °C

Procedure:
A stirred mixture of 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone (6.2 g., 0.023 mole), potassium carbonate (7.3 g.), ethyl bromoacetate (8.5 g.) in DMF (70 ml.) is warmed in an inert atmosphere at 55° C. for one hour, then treated with water (60 ml.) and 10N sodium hydroxide (10 ml.) and heated on a steam bath for 1.5 hours. The reaction mixture is poured into water, acidified, extracted with ether, washed with water and dried over magnesium sulfate. Following evaporation of the ether there is obtained 5.1 g. of (1-oxo-2-methyl-2-isopropyl-6,7-dichloro-5-indanyloxy) acetic acid which melts at 156°-157°C. after recrystallization from nitromethane.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([C:14]#N)=[CH:4][CH:3]=1.C(O)=[O:17]>[Ni]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=[O:17])=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc(C#N)c2CC1
Reactant: O=CO
Agent: [Ni]
Product: CN1CCc2c(Cl)ccc(C=O)c2CC1

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile (3.1 g, 14 mmol) in 90% formic acid (40 ml) was treated with Raney® nickel (3.1 g), stirred and heated to reflux for 3 hours. Additional Raney® nickel (17 g) and 90% formic acid (85 ml) were added over the next 12 hours and the mixture was stirred for an additional 3 hours. The mixture was cooled, filtered and the filter cake washed with 45% formic acid. The filtrate was concentrated, basified with 10% sodium hydroxide, extracted with ethyl acetate and the organic phase was washed, dried and concentrated to give 3 g of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde.
Reaction SMILES: [H-].[Li+].[CH3:3][N:4]([CH3:16])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:6].[ClH:17].[CH:18]([N:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][CH2:23][Cl:24])([CH3:20])[CH3:19]>O1CCOCC1>[ClH:24].[ClH:17].[CH3:3][N:4]([CH3:16])[C:5]([N:7]([CH2:23][CH2:22][N:21]([CH:25]([CH3:27])[CH3:26])[CH:18]([CH3:20])[CH3:19])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:6]
Reactant: Cc1cc(C)nc(NC(=O)N(C)C)c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)c1
Yield: 44.1 %

Procedure:
To a suspension of lithium hydride (0.65 g, 80 mmoles) in dry dioxane (65 ml) under nitrogen atmosphere is added N,N-dimethyl-N'-(4,6-dimethyl-2-pyridyl)urea (5.8 g, 30 mmoles) and the mixture is heated to reflux for three hours. 2-Diisopropylaminoethyl chloride hydrochloride (6.0 g, 30 mmoles) is added cautiously in small portions and refluxing continued for twenty-four hours. The reaction mixture is cooled, salts filtered off and solvent evaporated. The residue is dissolved in methylene chloride and the product is extracted into dilute aqueous hydrochloric acid (10%). This solution is filtered through charcoal, made basic with saturated sodium carbonate, and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate, filtered and evaporated. The crude product (8.3 g) is taken up in diethyl ether, insoluble material is removed by filtration and hydrogen chloride gas is bubbled into the filtrate. The precipitated salt is collected and recrystallized from isopropanol to give 5.2 g (44.0% yield) of product, m.p. 182°-186° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1)[CH3:6]>S(=O)(=O)(O)O>[CH2:5]([N:7]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([C:13]([F:15])([F:14])[F:16])=[N:8]1)[CH3:6]
Reactant: CCn1nc(C(F)(F)F)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCn1nc(C(F)(F)F)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 30 mL of concentrated sulfuric acid and 30 mL of concentrated nitric acid was added slowly with stirring at 0° C. to a solution of 18.9 g (106 mmol) of 1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 70 mL of concentrated sulfuric acid. When the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 72 hours. It was then poured slowly onto 500 g of ice. The resultant mixture was extracted twice with 100 mL portions of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 20.4 g (86 percent of theory) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:16][CH3:17])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)CCC>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:16][CH3:17])[C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccccc1N
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Agent: Cl
Solvent: CCCCO
Product: COc1ccccc1N1CCc2c(C)nc3c(OC)cccc3c21
Yield: 19.4 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline (2.70 g, 10 mmol) and 2-methoxyaniline hydrochloride (1.60 g, 10 mmol) in 1-butanol (40 ml) were heated at reflux for 6 hours then the solvent evaporated, the crude product taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Trituration with ether and recrystallisation from aqueous methanol gave 1-(2-methoxyphenyl)-4-methyl-6-methoxy-2,3-dihydropyrrolo[3,2-c]quinoline (0.62 g, 19%), m.p. 168°-169°.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30]([C:34]#[N:35])([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:28][CH2:29][C:30]([C:34]#[N:35])([CH3:33])[CH2:31][CH2:32]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
The 1.55 mL of benzo[d][1,3,2]dioxaborole (443 mg, 3.69 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (780 mg, 1.85 mmol) and 0.74 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (205 mg, 0.74 mmol) in toluene (18 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 674 mg (86%) as a mixture of diastereomers. 1H NMR (500 MHz, CD3OD) δ 5.89 (s, 1H), 5.10-5.05 (m, 1H), 4.13-4.05 (m, 1H), 3.78 (dt, J=11.7, 3.7 Hz, 1H), 3.06 (d, J=12.2 Hz, 1H), 2.86 (d, J=12.2 Hz, 1H), 2.63 (s, 3H), 2.51 (s, 3H), 1.94-1.86 (m, 3H), 1.79-1.73 (m, 1H), 1.46 (s, 3H), 1.24 (d, J=6.1 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H). UPLC (M+H)=426.3.