Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][N:6]=1)(=O)C.Cl.[CH3:13][CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15]Cl>>[CH3:13][CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][NH:4][C:5]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][N:6]=1
Reactant: CC(CCl)CN(C)C
Reactant: CC(=O)Nc1ncc(Cl)cn1
Agent: Cl
Product: CC(CNc1ncc(Cl)cn1)CN(C)C

Procedure:
Following the procedure of Example 1 part A using 2-acetamido-5-chloropyrimidine and 2-methyl-3-dimethylaminopropyl chloride hydrochloride, there is obtained 2-(2-methyl-3-dimethylamino-propylamino)-5-chloropyrimidine.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C[N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:14]([CH2:19][CH3:18])[CH2:15][CH3:16])=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 70.5 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g) and methylpiperazine (9.8 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-diethylaminobenzonitrile (12.7 g), melting point: 83–85° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5].[F:27][C:28]1[CH:29]=[C:30]([F:50])[C:31]2[N:32]([CH:34]=[N:35][C:36]=2[Sn](CCCC)(CCCC)CCCC)[CH:33]=1>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:36]3[N:35]=[CH:34][N:32]4[CH:33]=[C:28]([F:27])[CH:29]=[C:30]([F:50])[C:31]=34)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)cc(F)c12
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)cc(F)c34)nc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (125 mg, 0.28 mmol) and 6,8-difluoro-1-tributylstannyl-imidazo[1,5-a]pyridine (458 mg, 0.62 mmol) were dissolved in DMF (2.5 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) and copper (I) iodide (11 mg, 0.058 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 1.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed twice over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 136 mg (89%) of 2-(6,8-difluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18](=N)[N:17]([CH3:20])[C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH:9]=1.Cl.[OH2:22]>>[NH2:16][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:18](=[O:22])[N:17]([CH3:20])[C:11]=2[N:12]=1
Reactant: O
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=N
Agent: Cl
Product: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of 6-(2-methylphenyl)-7-imino-8-methyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamine (0.30 g) from Example 8 and concentrated HCl (0.6 mL) was added water (11 mL). The reaction mixture was refluxed for 20 hours, then allowed to cool to room temperature. The white precipitate from the reaction mixture was filtered and washed with water. The product was dried in vacuo to give 0.21 g of 2-amino-6-(2-methylphenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one; mp 239°-241° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:36])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methoxyphenyl isocyanate (91 mg, 0.63 mmoles) the title compound was isolated as a white solid. Yield; 48 mg (24%); (M+H)=492.3
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[O:13][C:14]([CH3:57])=[C:15]([CH2:17][O:18][C:19]2[CH:56]=[CH:55][C:22]([CH2:23][N:24]3[CH:28]=[C:27]([C:29](OCC)=[O:30])[C:26]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[N:45]=[C:46]([C:50]6[O:51][CH:52]=[CH:53][CH:54]=6)[O:47][C:48]=5[CH3:49])=[CH:38][CH:37]=4)=[N:25]3)=[CH:21][CH:20]=2)[N:16]=1.O>O1CCCC1>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[O:13][C:14]([CH3:57])=[C:15]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]5[N:45]=[C:46]([C:50]6[O:51][CH:52]=[CH:53][CH:54]=6)[O:47][C:48]=5[CH3:49])=[CH:40][CH:41]=4)=[N:25]3)=[CH:55][CH:56]=2)[N:16]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Lithium aluminium hydride (0.98 g) was added to a solution of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylate (19.16 g) in tetrahydrofuran (75 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]methanol (17.25 g, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].C1(C)C=CC=CC=1>C(N(CC)CC)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a suspension of 5.000 g of methyl 3-hydroxybenzoate, 6.955 g of 4-nitrophenyl chloroformate, and 100 mL of toluene was added 4.81 mL of triethylamine at room temperature, followed by stirring overnight. The insolubles were removed by filtration, and as solvent was removed by distillation under reduced pressure to obtain 5.948 g of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a pale yellow solid. To a mixture of 100 mg of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate, 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, and 4 ml of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate as a pale yellow oily compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]([Mg]Br)#[CH:12].Cl.C(OCC)C>C1COCC1>[C:5]1([C:1]([OH:4])([CH2:11][CH3:12])[C:2]#[CH:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(O)(CC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of propiophenone in THF (0.2 ml, 1.505 mmol) is slowly added dropwise at room temperature with stirring to a solution of ethynylmagnesium bromide (4 ml, 2.0 mmol, 0.5 M in THF) in THF (5 ml). The slightly yellow reaction solution was stirred at RT for 1 h. The reaction mixture is acidified using 1N HCl, during which a turbidity initially formed which disappeared with an increase in the pH into the acidic region. Diethyl ether was added to the solution, the aqueous phase was separated off, and the organic phase was extracted once with water. The organic phase was dried using sodium sulfate, filtered off and evaporated to dryness, giving 3-phenylpent-1-yn-3-ol (233 mg, 0.001 mol) in 65% yield. The crude mixture is reacted further without further purification.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:51][C:52]([C:54]1[N:55]=[C:56]([CH2:60][CH2:61][O:62][CH3:63])[S:57][C:58]=1[NH2:59])=[O:53])[CH3:50].Br[C:65]1[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=1>O1CCOCC1.C1COCC1>[CH2:49]([O:51][C:52]([C:54]1[N:55]=[C:56]([CH2:60][CH2:61][O:62][CH3:63])[S:57][C:58]=1[NH:59][C:65]1[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=1)=[O:53])[CH3:50]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1nc(CCOC)sc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(CCOC)sc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
A microwave vial was charged with Pd2dba3-chloroform complex (0.09 g, 0.09 mmol), Xantphos (0.17 g, 0.30 mmol) and cesium carbonate (1.00 g, 3.06 mmol), sealed and flushed with argon. A solution of 5-amino-2-(2-methoxy-ethyl)-thiazole-4-carboxylic acid ethyl ester (0.40 g, 1.75 mmol) and 3-bromopyridine (0.28 g, 1.75 mmol) in dioxane (5.80 ml) was degassed by sonicating and bubbling with argon, then transferred to the reaction vial. After stirring at room temperature for 5 min, the reaction mixture was irradiated in a microwave oven at 150° C. for 10 min. The mixture was diluted with THF, filtered and the mother liquors evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.18 g, 40%), MS (ISP): m/e=308.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/Br)=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4].[CH3:25][S-:26].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[S:26][CH3:25])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/SC
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (0.915 g, 2.196 mmol) was dissolved in DMSO (10 mL) and sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 min at ambient temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was diluted with petroleum ether to decrease the solubility of residual DMSO, washed with water thrice, filtered and concentrated. The product was purified by flash chromatography (hexane/ethyl acetate gradient) to provide the title compound (0.510 g, 60.5% yield) as a yellow solid: 1H NMR (CDCl3) δ 7.63 (dd, 1H), 7.19 (dd, 1H), 6.74 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:15])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:15])[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Br)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Ethyl chloroformate (15.91 g) was added dropwise to a solution of 4-bromo-2-fluoroaniline (25.33 g) and pyridine (21.06 g) in methylene chloride (260 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, it was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from ethyl acetate-n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-2-fluorophenyl)carbamate (34.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[NH:9][N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5].Cl[CH2:32]Cl.CI>O>[CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[N:9]([CH3:32])[N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5]
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)Nc2n[nH]c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Solvent: CI
Solvent: O
Product: Cc1ccc(C(=O)Nc2nn(C)c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving the compound 2,4-dimethyl-N-[8-(pyrrolidin-1-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizin-3-yl]benzamide (A35-M1-B8, Entry 200, Table III), obtained as described in the example 9, in dichloromethane 2 equivalent of methyl iodide were added. After four hours of stirring at room temperature, water was added and the phases were separated. The organic layer was Dried over Na2SO4 and the crude was purified through preparative HPLC. LCMS m/z 418 [M+H]+@ Rt2.87 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)s1
Yield: 73.6 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol) 5-methyl-2-thienoic acid, 13.0 mg (74%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccccc1OC(F)(F)F
Product: FC(F)(F)Oc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethoxy)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 165. LRMS (ES)+: 436.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[H-].[Na+].Br[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[N+:23]([O-:25])=[O:24]>O>[N:1]1([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1oc2ccccc2c1Br
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1oc2ccccc2c1-n1ccnc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 0.1 g. (12 mmole) of imidazole in 20 ml. of N,N-dimethylformamide is added 0.5 g. (12 mmole) of 57.6 percent suspension of sodium hydride in mineral oil. After cooling to 20° C., 2.4 g. (10 mmole) of 3-bromo-2-nitrobenzofuran in 20 ml. of N,N-dimethylformamide is added. After stirring 45 minutes, the mixture is heated on a steam bath for 15 minutes, then 50 ml. of water are added. Cooling and filtration provide yellow needles of 3-(N-imidazolyl)-2-nitrobenzofuran, m.p. 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:15][CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]1[C:6]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=2)[N:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Temperature: 90 °C

Procedure:
6-(2-Chlorobenzoyl)-5-(2-nitroethenylamino)indan (4.8 g) was added in small portions to a solution of DBU (4.8 g) in benzene (50 ml) with heating at 90° C. The mixture was refluxed for 30 minutes and, then, washed with 2N HCl and water and dried (MgSO4). The solvent was then distilled off to give crystals of 4-(2-chlorophenyl)-7,8-dihydro-3-nitro-6H-cyclopenta[g]quinoline. The crystals were collected by filtration and washed with methanol (4.50 g, 99.1%). Recrystallization from ethanol gave light brown prisms, mp. 175°-176° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].O>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCOCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-4-benzyloxazolidin-2-one (4.4 g, 25 mmol) in dry tetrahydrofuran (20 ml), cooled to -78° C., was added n-butyllithium (2.5M solution in hexane, 10 ml, 25 mmol) dropwise. Another 20 ml of tetrahydrofuran was added to facilitate stirring. A solution of ethoxyacetyl chloride (3.0 g, 25 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at -78° C. for 30 minutes, then warmed to room temperature, poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated to a yellow oil (4.3 g, [α]D =56.7°).
Reaction SMILES: [OH:1][CH:2]([CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([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)[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCCC(O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCCC(=O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of 49 (233 mg, 0.374 mmol) in CH2Cl2 (1 mL) was treated with PCC (121 mg, 0.561 mmol) at room temperature. Stirring was continued for 2 h. The mixture was diluted with Et2O, and the mixture was applied onto a plug of silica. The solid was washed with Et2O. The sample was concentrated, and the oily residue was chromatographed [silica, hexanes/ethyl acetate (10:1) to yield a colorless oil (166 mg, 71%): 1H NMR δ 1.82-1.88 (m, 4H), 2.55-2.58 (m, 4H), 3.65-3.72 (m, 4H), 7.43-7.45 (m, 12), 7.69-7.71 (m, 8H).
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2B2OC(C)(C)C(C)(C)O2)=[N:8]1.[Cl:25]C1C(C)=C(C=CC=1)N.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.N(OCCC(C)C)=O>>[Cl:25][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[N:7][NH:8]2
Reactant: Cc1c(N)cccc1Cl
Reactant: CC1(C)OB(c2cccc3nn(C4CCCCO4)cc23)OC1(C)C
Agent: CC(=O)[O-]
Agent: CC(C)CCON=O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: Clc1cccc2[nH]ncc12

Procedure:
Scheme 3 shows the synthesis of 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 starting by cyclization of 3-chloro-2-methylaniline 11 with potassium acetate, acetic anhydride, and isoamyl nitrite to yield 4-chloro-1H-indazole 12. The indazole nitrogen of 4-chloro-1H-indazole 12 was protected as tetrahydropyranyl (THP) with 3,4-dihydro-2H-pyran, and pyridinium p-toluenesulfonate in dichloromethane to yield 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 13 and a minor amount (about 10%) of the THP regioisomer, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The mixture was reacted with PdCl2(PPh3)2, tricyclohexylphosphine, bis(pinacolato)diboron, and potassium acetate in DMSO and heated to 130° C. for 16 hours to give 10, containing a minor amount (about 10%) of the THP regioisomer, 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
Reaction SMILES: Cl[Si:2]([CH3:9])([CH3:8])[CH2:3][CH:4]([CH3:7])[CH2:5]Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:8][Si:2]1([CH3:9])[CH2:3][CH:4]([CH3:7])[CH2:5][N:13]1[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: CC(CCl)C[Si](C)(C)Cl
Product: C=CCN1CC(C)C[Si]1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 1,1,4-trimethyl-2-allyl-2-aza-silacyclopentane was prepared as follows. Chlorodimethyl(3-chloro-2-methylpropyl)silane (100 g, 0.54 mol) was slowly added to 211.73 g (3.71 mol, 6.87 eq) of undistilled allyl amine resulting in an exothermic reaction. This reaction mixture was stirred at room temperature for 15 hours, heated to reflux at atmospheric pressure for 72 hours, and heated to 120° C. under about 50 psig pressure for 16 hours. The following GC-MS ratios shown in Table II exemplified the reactions progression and the spectra observed were as shown.