Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].OS(O)(=O)=O.O=S(=O)=O>>[F:8][C:7]([F:10])([F:9])[C:1]1[CH:6]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1

Procedure:
The m-trifluoromethylbenzenesulfonyl chloride starting material was prepared by reacting benzotrifluoride with chlorosulfonic acid in the presence of oleum (65% SO3), according to the method described in Chemical Abstracts 75, 19942d, (1971); German Offen. No. 1,954,448.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1I.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:11])[NH:9][N:10]=[C:4]3[C:3]=2[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
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: C1COCCO1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 150 °C
Yield: 51.7 %

Procedure:
To a stirring mixture of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.9 mmol) in 15 mL dioxane and 5 mL of water at 20° C. was added 4-chlorophenylboronic acid (1.4 g, 8.8 mmol), K2CO3 (0.8 g, 5.9 mmol), and tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol). The resulting reaction mixture was degassed and then heated in a microwave reactor at 150° C. for 40 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by trituration with methylene chloride to obtain the title compound (0.52 g, 1.5 mmol) as a light yellow solid. MS: [M+H]+=356. 1H NMR (CD3OD): δ 7.89 (d, J=1.9 Hz, 1H), 7.37-7.24 (m, 8H), 5.48 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:19])[CH2:8]/[CH:9]=[CH:10]/[C@H:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@@H:11]([CH3:18])[CH2:10][CH2:9][CH2:8][C@@H:7]([CH3:19])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17]
Reactant: CCOC(=O)C[C@@H](C)/C=C/C[C@@H](C)COC(C)(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](C)CCC[C@@H](C)COC(C)(C)C

Procedure:
A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30 ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperature, for 2 hours during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered off and washed with ethyl acetate. Concentration of the combined filtrate and washes in vacuo followed by evaporative distillation afforded 1.045 g. (95%) of saturated ester (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloctanoate as a colorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:30])([C@H:27]([SH:29])[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH:2]([S:29][C@H:27]([CH3:28])[C@:20]([C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12])([OH:30])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH3:5])#[N:4]
Reactant: CC(Br)C#N
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C#N)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
134 mg (1.00 mmole) of 2-bromopropionitrile and 69 mg (0.50 mmole) of potassium carbonate were added to a solution of 143 mg (0.50 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 3 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour under an atmosphere of nitrogen. The reaction mixture was then dissolved in benzene, and the resulting solution was washed, in turn, with water and with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure, after which the resulting oily residue was purified by preparative thin layer chromatography on silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the developing solvent, to afford 57 mg of stereoisomer A of the title compound (having the lower polarity) as an oil and 72 mg of stereoisomer B of the title compound (having the higher polarity) as crystals; these crystals were recrystallized from a mixture of benzene and hexane to give a pure specimen melting at 66°-68° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:33][CH2:34][CH3:35])[CH:5]=[C:6]([C:9]1[N:10]=[N:11][N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:13]=1)[C:7]#[N:8])[CH2:2][CH3:3].CO.Cl>O=[Pt]=O.C1COCC1>[CH2:33]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]([C:9]1[NH:13][N:12]=[N:11][N:10]=1)[CH2:7][NH2:8])[CH2:34][CH3:35]
Reactant: CCCC(C=C(C#N)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)CCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(CCC)CC(CN)c1nnn[nH]1
Reaction time: 30 h
Yield: 51.2 %

Procedure:
To a solution of 4-propyl-2-(2-trityl-2H-tetrazol-5-yl)-hept-2-enenitrile (1.60 g, 3.47 mmol) in 50 mL 1:1 MeOH:THF was added PtO2 (0.1 g), concentrated HCl (1.09 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 30 h. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2), followed by a second column using the same conditions, provided 0.40 g (51%) of 4-propyl-2-(1H-tetrazol-5-yl)-heptylamine as a colorless solid. 1H NMR (D2O) δ 3.29 (m, 1H, —CHCH2NH2), 3.09 (m, 2H, —CH2NH2), 1.56 (m, 1H, —CHCHHCH—), 1.37 (m, 1H, —CHCHHCH—), 0.80-1.07 (m, 9H, —CH2CHCH2—, —CH2CH2—), 0.58 (t, J=6.6 Hz, 3H, CH3—), 0.47 (t, J=6.6 Hz, 3H, CH3—). Anal. Calcd for C11H23N5: C, 58.63; H, 10.29; N, 31.08. Found: C, 57.87; H, 10.04; N, 30.73.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CS(C)=O>[C:14]([O:13][C:12](=[O:18])[NH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH:2]=[O:1])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 1.63 g of tert-butyl 3-hydroxy-1-phenylpropylcarbamate (Formula 11) in 15 mL of dimethyl sulfoxide (DMSO) was added 2.72 mL of triethylamine. The solution was cooled to 0° C. and 3.1 g of sulfur trioxide pyridine complex in 15 mL of DMSO was added. The reaction mixture was stirred at room temperature for 1 hour then poured onto ice-water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 10% acetic acid, water, 5% sodium bicarbonate, and brine, dried over sodium sulfate and concentrated. Column chromatography (40% ethyl acetate/hexane) gave 1.2 g (74%) of tert-butyl-3-oxo-1-phenylpropylcarbamate (Formula 12) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 2.89-2.96 (m, 2H), 5.23 (br, 1H), 5.32 (br, 1H), 7.27-7.37 (m, 5H), 9.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH:40]=[CH:39][C:38]([NH:41][CH:42]([CH3:44])[CH3:43])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][C:34]([N:36]1[CH:40]=[CH:39][C:38]([N:41]([C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:42]([CH3:44])[CH3:43])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)Nc1ccn(C(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccn(C(=O)OC(C)(C)C)n1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (100 mg, 0.2 mmol), 3-isopropylamino-pyrazole-1-carboxylic acid tert-butyl ester (54 mg, 0.24 mmol), TEA (0.88 mL) in THF was stirred at RT for 2 hours and then purified by flash column to give 3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CCOC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 52.3 %

Procedure:
Beginning with 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 2.96 mg (0.0273 mMol) ethyl chloroformate, 4.1 mg (52%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](C2C=CC=CC=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: Cc1cccc(C(N)=O)c1Br
Product: Cc1cccc(C(N)=O)c1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
Prepared from 2-bromo-3-methylbenzamide by the procedure of Example 135 using Intermediate 2 in Step 2. m/z (ES+) 397 [(M-NH2)+].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperazin-1-yl-1H-indole (71 mg, 0.18 mmol) in tetrahydrofuran is treated sequentially with benzyl bromide (21 μl) and triethyl-amine (75 μl), shaken at room temperature for 16 hr and concentrated in vacuo to give a residue. The residue is purified by RP-HPLC to give the title product, 37 mg, identfied by HPLC and mass spectral analyses (2.81 min; 432 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:4][CH:3]=1.[Cl:12]C1C=CC(I)=CC=1Cl>>[Cl:12][C:7]1[CH:6]=[C:5](/[CH:8]=[CH:9]/[CH:10]=[O:11])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: O=C/C=C/c1ccc(Cl)cc1
Product: O=C/C=C/c1ccc(Cl)c(Cl)c1
Yield: 58 %

Procedure:
The same synthetic procedure as described for intermediate 5d, but starting from 1,2-dichloro-4-iodobenzene gave 58% of the title compound which was characterised as follows:
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1O
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A well stirred suspension of 3.6 g (0.012 mole) of 1,3-dihydro-3-hydroxy-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10°, at which temperature all of the solid went into solution. The reaction mixture was poured into 400 ml of ice water, and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-heptane to give 3.0 g (83%) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 174°-175° (dec.); 1H nmr (DMSO-d6) δ 5.90 ppm (d, J=57 Hz, 1H), 7.3-7.7 ppm (m, 6H), 8.07 ppm (d, J=2.5 Hz, 1H) and 8.45 ppm (d, d, J=9.0, 2.5 Hz, 1H); 19F nmr (DMSO-d6) δ -161.4 ppm (d, J=57 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([CH2:32][CH2:33][CH2:34][OH:35])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@@:18]([CH2:32][CH2:33][CH2:34][O:35][S:37]([CH3:36])(=[O:39])=[O:38])([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:19]1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)N1CCCC(CCCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Diisopropylethylamine (1.6 mL, 9.18 mmol) was added to a solution of alcohol (10) (1.2 g, 3.06 mmol 3.0 eq) in CH2Cl2 (30 mL) followed by MsCl (0.28 mL, 3.67 mmol, 1.2 eq). The solution was stirred at room temperature for 2 hours, then quenched with water and diluted with CH2Cl2 (200 mL). The organic layer was washed with brine, 1N HCl, saturated NaHCO3, and dried over MgSO4. The crude oil was purified by flash chromatography (CH2Cl2—MeOH/95:5) to give light yellow solid (1.43 g, 99.3%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[O:3].[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21]2)[NH:18][CH:19]=1)[CH3:14]>C1COCC1>[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]2[C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[O:3])[NH:18][CH:19]=1)[CH3:14]
Reactant: CCc1c[nH]c(C2Cc3ccccc3N2)n1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCc1c[nH]c(C2Cc3ccccc3N2C(=O)Nc2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1-Isocyanato-2-nitro-benzene (0.002 mol) was added to a solution of intermediate (15) (0.016 mol) in THF (10 ml). The mixture was stirred at room temperature under argon for 5 hours. The mixture was diluted with hexanes, filtered, and allowed to dry, yielding 0.34 g of 2-(4-ethyl-1H-imidazol-2-yl)-2,3-dihydro-N-(2-nitrophenyl)-1H-indole-1-carboxamide (compound 77, mp. 208-209° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=1)#[N:16]
Reactant: N#Cc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(O)c1
Product: N#Cc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1
Yield: 62.2 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1 H), 7.10 (t, J=8.1 Hz, 1 H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1 H), 7.33 (t, J=2.1 Hz, 1 H), 7.45 (dt, J=1.2 and 7.8 Hz, 1 H), 7.54 (t, J=8.1 Hz, 1 H), 8.08 (d, J=3.3 Hz, 1 H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1 H), 8.39 (t, J=2.1 Hz, 1 H), 8.58 (s, 1 H, NH), 8.84 (s, 1 H, NH); 19F NMR (282 MHz, acetone-d6): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS (m/e): 322.59 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:30]1([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)[CH:31]=[CH:32][C:33]([NH:36][C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:38])=[CH:34][CH:35]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 513.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][Br:15]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(C(C)=O)cc(Cl)c(CBr)c1Br
Temperature: 25 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (3.3 g, 12 mmol), N-bromosuccinimide (2.2 g, 13 mmol), and benzoyl peroxide (0.15 g, 0.60 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled to room temperature and concentrated. The resulting residue was diluted with ethyl acetate and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for C10H10Br2ClO2 (M+H)+: m/z=355.1. found: 355.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([OH:17])=[O:16])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@H](Nc1ccc(Br)cc1)C(=O)O
Temperature: 95 °C

Procedure:
To 1,4-dibromobenzene (16.1 g, 68.25 mmol), L-leucine (2.984 g, 22.75 mmol), potassium carbonate (4.71 g, 34.13 mmol), and copper iodide (650 mg, 3.41 mmol) was added dry DMA (N,N-dimethylacetamide, 100 mL). The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 and the product was extracted with EtOAc (3×), dried on Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex/AcOH, 3/7/1% then 4/6/1%) to afford (2S)-2-(4-bromoanilino)-4-methylpentanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]1>CN(C=O)C>[CH3:24][C:20]1[CH:21]=[C:22]([CH3:23])[N:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1cc(C)n(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2nc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.2 g, 8.8 mmol) was dissolved in anhydrous DMF (50 mL), then potassium carbonate (3.6 g, 26.3 mmol) and 1-(bromomethyl)-3,5-dimethyl-1H-pyrazole (3.0 g, 15.8 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 2-{[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (218 mg, 10% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 5.81 (s, 2H), 5.83 (s, 1H), 6.07 (bs, 1H); LRMS (ES+) m/z 251 (50%, M+1).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11]>C(O)(=O)C.CN(C)C=O>[Cl:4][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([F:6])[C:15]=1[OH:16])[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1ccc(O)c(F)c1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (4.7 mL) is added to a solution of 3-fluoro-4-hydroxy-benzoic acid (2.97 g) in acetic acid (20 mL) stirred at 50° C. in N,N-dimethylformamide (3 mL) at room temperature. The resulting solution is stirred for 2 h, prior to the addition of another portion of sulfuryl chloride (1.0 mL). The solution is stirred at 60° C. for another 1.5 h and then cooled to ambient temperature. The solution is poured into ice-cold water and the precipitate formed is separated by filtration, washed with ice-cold water, and dried at 50° C. to afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH:16]=[O:17])=[CH:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BH4-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([CH2:16][OH:17])=[CH:14][CH:13]=[N:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-n2nccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2nccc2CO)cc1
Reaction time: 0.5 h

Procedure:
To a solution of crude 2-(4-methanesulfonyl-phenyl)-2H-pyrazole-3-carbaldehyde from Part A in methanol (10 mL) was added sodium borohydride (0.15 g, 4 mmol) in one portion. After 30 min at room temperature, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (sodium sulfate) and concentrated affording [2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methanol. The crude material was used without further purification.