Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.[CH2:6]=O.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>>[CH2:1]([N:4]1[CH2:6][CH:12]2[CH2:8][CH:9]1[CH:10]=[CH:11]2)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C1=CCC=C1
Reactant: C=O
Agent: Cl
Product: C=CCN1CC2C=CC1C2
Yield: 91 %

Procedure:
According to Variant A, 144 g (2.5 moles) of allyl amine are neutralized with hydrochloric acid solution, are reacted with 187.5 g (2.5 moles) of 40% formalin solution and 198 g (3.0 moles) of cyclopentadiene, and are worked up. After vacuum distillation 313 g of a product containing 98% (V) are obtained. This corresponds to a yield of 91% of theoretical.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:4].N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][C@H:3]([C:5]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)C1(O)CCCC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)C2(O)CCCC2)cc1
Reaction time: 48 h
Yield: 169.5 %

Procedure:
A mixture of 3a (1.79 g, 12.4 mmol), pyridine (5 mL), and p-toluenesulfonyl chloride (4.26 g, 22.3 mmol) in dichloromethane (40 mL) was stirred below 10° C. for 2 days. The reaction mixture was poured into copper (II) sulfate solution and extracted with diethyl ether. The combined organic layers were washed with copper (II) sulfate solution, water, sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 6.27 g of an oily material, which was purified by column chromatography (silica gel 60 g, ethyl acetate in n-hexane, 5-33%) to give 3.74 g (quantitative) of 4a as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:19](=[O:21])[CH3:20])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CN
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(Br)ccc1CNC(C)=O
Reaction time: 1 h

Procedure:
To 4-bromo-2-ethyl-benzylamine (700 mg, 3.3 mmol) and triethylamine (600 μL, 4.3 mmol) in dichloromethane (5 mL) at room temperature was added acetyl chloride (310 μL, 4.5 mmol). The solution was stirred for 1 h, diluted in water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid (820 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 1.20 (t, J=7.54 Hz, 3 H) 2.00 (s, 3 H) 2.62 (q, J=7.54 Hz, 2 H) 4.38 (d, J=5.46 Hz, 2 H) 5.59 (s, 1 H) 7.09 (d, J=8.10 Hz, 1 H) 7.26–7.31 (m, 1 H) 7.34 (d, J=1.88 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C([N:33]([CH2:36]C)CC)C.C[N:39](C)C=O>>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:29][CH:30]=1)[C:36]([NH2:33])=[NH:39]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN)cc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNC(=N)N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg of 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are dissolved in 5 ml of dimethylformamide and 300 ml of triethylamine are added. Then 700 mg of 3,5-dimethylpyrazol-1-carboxylic acid amidine in 5 ml of dimethylformamide are added. After one day of stirring at room temperature the reaction solution is concentrated by rotary evaporation. The residue is dried at 100° C. in vacuo.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:27]1([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[CH2:29][CH2:28]1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:36][CH:33]4[CH2:34][CH2:35][N:30]([CH:27]5[CH2:29][CH2:28]5)[CH2:31][CH2:32]4)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: OC1CCN(C2CC2)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
N-benzyl-N-methyl-4-oxopiperidiumbromide (3.68 g) in water (6 ml) was added portionwise over 30 minutes to a stirred mixture of N-cyclopropylamine (0.404 g) and potassium carbonate in ethanol (15 ml) at 75° C. The mixture was stirred at 75° C. for 45 minutes. The reaction mixture was evaporated, took up into water (20 ml) and extracted into methylene chloride. The organic extracts were combined and concentrated under reduced pressure and the residue was triturated with ether and the soluble fraction was isolated by evaporation (1.11 g) to give N-cyclopropyl-4-piperidone; NMR Spectrum: (CDCl3) 0.50 (m, 4H), 1.73 (m, 1H), 2.40 (t, 4H), 2.91 (t, 4H). B) Sodium borohydride (0.085 g) was added to a stirred solution of N-cyclopropyl-4-piperidone (0.312 g) in ethanol under an atmosphere of argon. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, took up into water (20 ml) and extracted into methylene chloride. The organic extracts were combined and concentrated under reduced pressure to give N-cyclopropyl-4-piperidinol (0.298 g); NMR Spectrum: (CDCl3) 0.50 (m, 4H), 1.35 (s, 1H), 1.55 (m, 2H), 1.86 (m, 2H) 2.34 (m, 2H), 2.89 (m, 2H), 3.70 (m, 1H). C) Using an analogous procedure to that described paragraph (A) in the portion of Example 15 which is concerned with the preparation of starting material, N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide was reacted with N-cyclopropyl-4-piperidol to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]-2-nitrobenzamide; Mass Spectrum: M+H+ 479.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 15 g (0.10 mole) of 2-chloro-3-nitro pyridine and 9.3 g (0.10 mole) of aniline were heated by means of an oil bath at about 120° C. for 30 min. The mass spectra of a sample taken at 15 min indicated presence mainly of the title compound. The product was partitioned between chloroform and aqueous basic solution (sodium hydroxide). The aqueous solution was washed twice more with chloroform. The chloroform extracts were washed once with a sodium chloride-sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to give 21.9 g of black oil which solidified on standing. The solid was triturated in 30-60 pet-ether for 1 hr. The remaining solid was filtered off and washed with the same solvent and air dired to give 18.7 g (87%). The solid was recrystallized from cyclohexane. Nuclear magnetic resonance confirmed the title compound, m.p. 172°-174° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:18])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[C:27]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[C:28]([O:30][CH3:31])=[O:29])=[N-]>C1C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([O:18][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COC(=O)[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 7.186 g, 22.6 mmol) and rhodium(II) acetate dimer (0.216 g, 0.452 mmol) in benzene (30 ml) was heated to reflux, and treated slowly with a solution of methyl 2diazo-2-(3,5-bis(trifluoromethyl)phenyl)-acetate [prepared by the method of R. T. Lewis et al. J. Org. Chem., 2000, 65, 2615] (7.7563 g, 24.86 mmol) in benzene (30 ml). After the addition was complete the mixture was concentrated in vacuo and the residue purified by flash column chromatography, eluting with 10-20% ethyl acetate/hexane to give a mixture of diastereomers (6.0 g, 2.6:1 ratio). The major diastereomer was separated by crystallisation with ethyl acetate/hexane to afford the title compound in two crops (3.81 g).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].[Cl-].[Al+3].[Cl-].[Cl-].[C:22]1([CH3:29])[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:29][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][C:27]=1[C:2]1[N:4]=[C:5]([C:27]2[CH:26]=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[N:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][C:13]=2[OH:14])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Oc1cccc(O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1

Procedure:
The title compound is prepared by the reaction of cyanuric chloride with m-xylene followed by reaction with resorcinol. Aluminum chloride is used as a reagent in both reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1cccc(F)c1O
Product: COc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17 mmol, prepared in Example 52, Step 2) to give 230 mg (66%) of a yellow oil. HRMS m/z calcd for C17H21FN4O3 (M)+ 348.1598, found 348.1602.
Reaction SMILES: C(Cl)(OC(F)F)C(F)(F)F.CN[C:13]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2Cl)[C:18](=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC=C(C)C=1NC1SCCCN=1.C[C@@:43]12[C@H:52]3CC[C@:55]4(C)[C:59](=[O:60])[C@H:58](F)[CH2:57][C@H:56]4[C@@H:51]3[CH2:50][CH:49]=[C:48]1[CH2:47]CCC2.[CH2:63]([OH:65])[CH3:64]>>[CH3:47][C:48]1[CH2:43][CH2:52][C@@H:51]([C:56]([CH3:57])=[CH2:55])[CH2:50][CH:49]=1.[C:63]([O:60][CH:59]([CH3:55])[CH3:58])(=[O:65])[CH2:64][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:13][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCO
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](F)C[C@@H]12
Agent: Cc1cccc(C)c1NC1=NCCCS1
Agent: FC(F)OC(Cl)C(F)(F)F
Product: C=C(C)[C@H]1CC=C(C)CC1
Product: CCCCCCCCCCCCCC(=O)OC(C)C

Procedure:
The mice were anesthetized with Isoflurane, and then were given an intramuscular injection of 0.1 mL solution of ketamine (50 mg/kg) and xylazine (10 mg/kg). Approximately 10 minutes after the i.m. injection (after the mice could not turn over when placed on their backs), the mice were treated with 12.3 μL of a mg/mL fluasterone/ethanol:limonene:isopropyl myristate solution to give a dose of 5 mg/kg. The mice were anesthetized and on their backs for approximately 30 minutes after application of fluasterone:ethanol:limonene:isopropyl myristate solution. One hour after the application of fluasterone solution, 2 μg of TPA dissolved in 0.2 mL of acetone was applied to the shaved area on the back of each mouse.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A from 2-fluoro-4-hydroxybenzoic acid and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 307.3
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-benzoic acid, the title compound was prepared as white powder. MS: m/e=403(M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 120 °C
Yield: 89.7 %

Procedure:
The mixture of 3-bromo-5-nitro-1H-indazole (484.1 mg, 2.0 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (927.7 mg, 1.0 eq), (PPh3)4Pd (0) (462 mg, 0.2 eq), Na2CO3 (2M, 3.0 mL, 3.0 eq) in dioxane (12 mL) was degassed and heated at 120° C. in a microwave-oven synthesizer for 2 h. The mixture was cooled to room temperature and filtered through a celite pad to remove Na2CO3 and catalyst. The celite pad was washed with EtOAc. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product tert-butyl 4-(5-nitro-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (618 mg, isolated yield 90%).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)=[CH2:23]>C(Cl)Cl>[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Br:1])=[CH:26][CH:25]=1)=[CH2:23]
Reactant: C=Cc1ccc(CO)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
Bromine (16.4 g, 103 mmol) was slowly added to a solution of triphenylphosphine (28.87 g, 110.1 mmol) in CH2Cl2 (260 mL) at 0° C. After 10 minutes, 4-vinylbenzyl alcohol (12.5 g, 93.3 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was triturated with petroleum ether (3×), and the ethereal solution was concentrated in vacuo. The residue was purified by flash chromatography (hexanes) to afford 4-vinyl-benzyl bromide (6.23 g). 1H NMR (400 MHz, CDCl3) δ7.32-7.45 (m, 4H), 6.72 (dd, 1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1Cl.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]2=[O:32])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1[N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]2=[O:32])[CH2:20][CH2:21]1
Reactant: CC(C)NC(=O)c1cnc(Cl)c(Cl)c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of step (i) (0.3 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.35 g) using the method of example 115 step (ii). Yield 0.187 g.
Reaction SMILES: [C:1]([C:9]1[CH:42]=[CH:41][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][NH2:45]>>[C:37]([O:36][C:34]([N:32]([CH3:33])[CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:41]=[CH:42][C:9]([C:1](=[N:45][O:44][CH3:43])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)N(C)C(=O)OC(C)(C)C
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)N(C)C(=O)OC(C)(C)C)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1B(O)O.CC([O-])(C)C.[K+]>COCCOC.CC(O)(C)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>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:5]2[CH:17]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCCN(CCC)c1cccc2nc(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CCCN(CCC)c1cccc2nc(-c3ccc(C)cc3C)cn12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 1.7 %

Procedure:
2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (prepared in example 61) (0.17 g, 0.57 mmol) was dissolved in 1,2-dimethoxyethane (DME) (1.5 mL). Pd(PPh3)4 (0.033 g, 0.028 mmol) was added and the reaction was stirred at 50° C. for 15 minutes. The solution was cooled and 2,4-dimethylphenylboronic acid (0.103 g, 0.69 mmol) in DME (1 mL) was added to the reaction mixture. KOtBu (0.128 g, 1.14 mmol) in tBuOH (1 mL) was also added to the reaction. The reaction was heated to 100° C. for 1 hr. The solution was filtered through paper and concentrated. Crude material was purified via reverse phase HPLC (acetonitrile containing 0.1% TFA/water containing 0.1% TFA) to obtain 3.1 mg of the title compound (2% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Na+].S(N1C=CN=C1)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[O:27][CH2:25][C@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc(F)c(C#N)c3)OC[C@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 13.2 mmol) in 100 mL of THF was stirred at 0° C. for 10 min, and then NaH (60%) (1.32 g, 33.0 mmol) was added at 0° C. The resulting white suspension was stirred vigorously at 0° C. for 5 min, then at r.t for 1 h. The reaction suspension was then recooled to 0° C., N-Tosylimidazole was added and the resulting solution was stirred for a further 10 min at 0° C. before being warmed again to r.t and stirred for 1 h. The reaction solution was then cooled once more to 0° C., and excess sodium hydride was carefully quenched by the slow addition of sat. NH4Cl solution. The resulting biphasic solution was partitioned between sat. NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the title compound: 1H-NMR (300 MHz, CDCl3) δ7.76˜7.79 (m, 1H), 7.49˜7.58 (m, 1H), 7.11˜7.15 (m, 1H), 7.16˜7.12 (m, 1H), 3.86˜4.06 (m, 2H), 3.33˜3.48 (m, 1H), 3.08˜3.17 (m, 1H), 2.80˜2.94 (m, 2H), 2.64˜2.74 (m, 2H), 2.29˜2.46 (m, 2H), 2.09˜2.20 (m, 1H), 1.40 (d, J=3.0 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CI.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH3:36])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A mixture of the crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step, MeI (18.2 g, 128 mmol) and K2CO3 (325 mesh, 17.7 g, 128 mmol) in DMF (100 mL) was stirred at room temperature for 70 min. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O (2×), dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.