Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1[C:40]([C:41]#N)=[C:39](N2CCC(C3N(CCNCC(C)C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:37][NH:36][CH2:35][CH:40]([CH3:41])[CH3:39])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CC(C)CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CC(C)CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[NH:15][C:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17]([OH:19])=[O:18])=[N:13][CH:12]=1.[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>C1COCC1>[CH2:26]([C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:16]([C:14]2[N:15]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:12][N:13]=2)[C:17]([O:19][C:2]([CH3:11])([CH3:3])[CH3:1])=[O:18])[O:18][CH2:17][CH2:16][O:28]1)[CH3:27]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCC(=O)CCCCCC(C(=O)O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CCCCCC(C(=O)OC(C)(C)C)c2ncc(-c3ccc4ccccc4c3)n2COCC[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 1, A3 in dry THF (0.06 M solution) at 0° C. was added NaH (60%, 1.5 eq.) portionwise, the resulting mixture was stirred for 1 hr and then SEM-Cl (1.5 eq.) was added dropwise. The solution was allowed to warm to RT and stirred for a further 3 hrs. The reaction was quenched by the addition of sat. aq. NH4Cl solution and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain D1 as a pale brown foam. 1H NMR (400 MHz, CDCl3) δ: 8.32 (1H, s), 7.91-7.75 (5H, m), 7.49-7.37 (2H, m), 5.43 (1H, d, J=10.9 Hz), 5.26 (1H, d, J=10.9 Hz), 3.90 (4H, s), 3.86 (2H, t, J=7.4 Hz), 3.57 (1H, t, J=8.1 Hz), 2.27-2.14 (2H, m), 1.67-1.57 (4H, m), 1.49 (9H, s), 1.41-1.27 (6H, m), 0.96 (2H, t, J=7.4 Hz), 0.87 (3H, t, J=7.5 Hz), 0.07 (9H, s). MS (ES) C35H52N2O5Si requires: 608, found: 609 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[C:7]([O:6][C:4]([C@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:2][NH:1][S:35]([C:31]1[S:30][CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])=[O:5])([CH3:9])([CH3:10])[CH3:8]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CNS(=O)(=O)c1cccs1)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
A solution of 0.504 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 20 ml of dichloromethane was cooled to 0° C. while stirring and 0.242 g of 2-thiophenesulphonyl chloride was added. The mixture was left to come to room temperature and was stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The ethyl acetate layer was washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with ether and there was obtained 0.487 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-[(2-thienyl)sulphonamido]ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=O)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.ClCCl>[F:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[C:5]=1[C:15](=[O:17])[CH2:14][CH:9]2[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CC(CC(=O)O)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CC1CC(=O)c2c(F)cc(F)cc21
Yield: 23.1 %

Procedure:
This compound was prepared in an analogous manner to that of Example 25d with the replacement of 3-(3-fluorophenyl)glutaric acid with 3-(3,5-difluorophenyl)glutaric acid (9.02 g, 36.9 mmol) and an increase of the heating time from 10 min to 30 min. Chromatography of the collected product on a column of Silica Gel 60 (51×450 mm) with methanol:dichloromethane (4:96) gave a material which was recrystallized from water to give 1.93 g (23%) of 2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid: m.p., 170-172° C.;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.P(Br)(Br)([Br:25])=O>BrCBr>[Br:25][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(O)c1cnc(Cl)nc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: BrCBr
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(Br)c1cnc(Cl)nc1Cl
Reaction time: 0.17 h

Procedure:
(±)-1-(2,4-Dichloro-pyrimidin-5-yl)-2-methyl-propan-1-ol (0.18 g; 0.83 mmol) (from Example 11a supra) was combined with N,N-diisopropyl-ethylamine (0.37 mL; 2.10 mmol) (Aldrich) and a small volume of dibromomethane (50 μL) (Aldrich) to help solubilize the mixture. Only a small amount of material remained insoluble. Neat phosphorus oxybromide (0.22 g; 0.85 mmol) (Aldrich) was added in one portion. Reaction mixture was stirred for 10 minutes and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M) gave (±)-5-(1-bromo-2-methyl-propyl)-2,4-dichloro-pyrimidine as a colorless oil. (Yield 79.5 mg; 33.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1.C(O)(=O)C.Br>O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A mixture of the title A compound, 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene (16.4 g, 60 mmol), acetic acid (AcOH; 100 mL) and aqueous 48% hydrobromic acid (HBr; 100 mL) is heated at 120° C. for 16 h. The mixture is cooled to RT, diluted with water (200 mL) and the precipitated product is collected by vacuum filtration, washed with water and hexanes and dried in vacuo to afford 3,5-dimethyl-4-(4′-hydroxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 6.62 (d, 2H, J=8.7), 6.77 (d, 2H, J=8.7), 8.0 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:19])([CH3:18])[CH2:12]OS(C)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:18])[CH2:12][O:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(R)-2-Chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole prepared in Example 11 (942.6 g, 3 mol) was suspended in ethyl acetate (9426 ml). DBU (494 ml, 3.3 mol) was added to the suspension, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (5 liters). The water layer was extracted with ethyl acetate (5 liters) twice. The organic phases were combined together, and the mixture was washed with a saturated saline solution (5 liters), dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole (600.7 g, yield 92%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(Cl)(=O)C1C=CC=CC=1.CN(C)C1C=CC([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=CC=1.[H-].[Na+].[Na].NCl>CN(C=O)C.N1C=CC=CC=1>[C:29]([NH:28][NH:7][C:6]1[CH:8]=[CH:9][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: CN(C)c1ccc(N)cc1
Agent: NCl
Agent: [H-]
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NNC(=O)c2ccccc2)cc1

Procedure:
Reaction of 4-dimethylaminoaniline with benzoyl chloride in the presence of pyridine and reaction of the resulting N-(4-dimethylaminophenyl)benzamide with sodium hydride in DMF followed by reaction of the resulting sodium salt with chloramine all according to the procedure described above in Example 65 affords N'-benzoyl-4-dimethylaminophenylhydrazine. Reaction of the latter with 3-phthalimidopropyl methyl ketone in refluxing ethanol using the procedure described above in Example 1 affords 1-benzoyl-5-dimethylamino-2-methyl-3-(2-phthalimidoethyl)indole, which on refluxing in ethylene glycol dimethyl ether in the presence of a molar excess of hydrazine hydrate affords 1-benzoyl-3-(2-aminoethyl)-5-dimethylamino-2-methylindole. The latter, on reaction with one mole of isopropyl bromide in refluxing acetone in the presence of sodium carbonate affords 1-benzoyl-3-(2-isopropylaminoethyl)-5-dimethylamino-2-methylindole.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH2:10][CH2:11][CH:12]([OH:13])[C:15]([F:17])([F:16])[F:14])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 65.9 %

Procedure:
Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (320 mg, 1.71 mmol) and (trifluoromethyl)trimethylsilane (298 mg, 2.10 mmol) were dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 1.0 ml, 1.0 mmol) and the mixture was then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulphate. The solvent was evaporated and the residue eluted down a flash chromatography column using 50% diethyl ether/isohexane as eluent to give 290 mg (66%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([NH:43][CH2:44][CH2:45][F:46])=O>>[F:46][CH2:45][CH2:44][NH:43][CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1
Reactant: O=C(CCl)NCCF
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNCCF)cc2)C(C)C)c1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (8.9 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH3:19])=[C:16]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:15]([C:32]#[N:33])=[N:14]1.C(N(C(C)C)CC)(C)C.C1C[O:46][CH2:45]C1.CCCCCCC.C(OCC)(=O)C>O>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH3:19])[CH2:20][CH:21]2[CH2:22][O:23][C:45](=[O:46])[O:24]2)=[C:16]([S:25]([C:28]([F:31])([F:29])[F:30])(=[O:26])=[O:27])[C:15]([C:32]#[N:33])=[N:14]1
Reactant: C1CCOC1
Reactant: CN(CC(O)CO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CC1COC(=O)O1)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.7 %

Procedure:
To a mixture of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2,3-dihydroxypropyl)(methyl)amino]-4-[(trifluoromethyl)sulfonyl]-1H-pyrazole-3-carbonitrile (0.20 g, 0.4 mmol) and diisopropylethylamin (0.14 g, 1.1 mmol) in THF (10 mL) phosgene-toluene solution (0.22 g, 20% COCl2, 0.4 mmol) was added. The mixture was stirred at 20-30° C. for 20 h. Extractive workup (heptane-ethyl acetate, water) and chromatography gave the title product (Compound 05-18, 0.14 g) as an oil; 1H-NMR: 2.88 (NMe), 3.35 and 3.45 (NCH2), 3.96 and 4.55 (CH2O), 4.82 (CHO), 7.87 (ArH) ppm; 19F-NMR: −63.8 (PhCF3); -78.8 ppm (SO2CF3).
Reaction SMILES: C(NS(C1C=CC([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=CC=1)(=O)=O)(=O)C.C(Br)C=C>CN(C=O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:20]2[CH2:19][CH2:18][C:17]3[C:16]([C:37]([NH2:39])=[O:38])=[N:15][NH:14][C:22]=3[C:21]=2[CH:23]=1)=[O:36]
Reactant: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Temperature: 25 °C
Yield: 106.7 %

Procedure:
To a stirring solution of the Cs+ salt of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (637 mg, 0.92 mmol) in DMF (8 mL) was added a solution of allyl bromide (111 mg, 0.92 mmol). The solution was stirred at room temperature for over the weekend and concentrated. To the mixture was added MeOH—H2O (2:1). A precipitate was formed. It was filtered to give a yellow solid of 1-(4-[acetyl(allyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (360 mg, 65%.)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:14]1[C:10]([CH3:9])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][C:13]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (1.77 g, 13.25 mmol) was added to a solution of ethyl 3,5-dimethyl-2-pyrrole carboxylate (2.11 g, 12.62 mmol) in chloroform (45 mL). The reaction mixture was stirred at room temperature for 24 h and then poured into 2 N NaOH. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. The crude solid was dissolved in hot MeOH, cooled to room temperature, and the precipitate was collected by filtration (493 mg, 19%). MS (ES) MH+: 174 for C9H12ClNO2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.Cl>[Si:17]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(CO)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
To a solution of 4-hydroxymethylbenzoic acid (1 g) in DCM (66 mL) was added imidazole (985 mg, 2.2 equiv) followed by the addition of t-butyldimethylsilyl chloride (TBSCl) (1.09 g, 1.1 equiv). The reaction mixture was stirred at room temperature for 3 days and was diluted with DCM (50 mL) and 1 N HCl. The aqueous phase was extracted with DCM, and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide the title compound (1.44 g, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:27]([NH:30][NH2:31])(=[O:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[C:27]([NH:30][NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH3:12])(=[O:29])[CH3:28]
Reactant: CC(=O)NN
Reactant: COc1cc(Br)ccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(=O)NNC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-2-methoxybenzoic acid (950.7 mg, 4.11 mmol) in 8 ml of DMF was treated sequentially with EDC (1183 mg, 6.17 mmol) and HOBT (945 mg, 6.17 mmol) and stirred at room temperature for 10 minutes. The reaction was then treated with acetic hydrazide (366 mg, 4.94 mmol) and stirred at room temperature overnight. The reaction was dissolved in EtOAc and washed sequentially with saturated bicarbonate solution and brine. The aqueous washes were extracted once with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a white solid (1.37 g crude).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].C([Li])CCC.[Br:15]Br>O1CCCC1>[Br:15][C:5]1[S:4][C:3]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C(=O)O
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a stirred solution of 3-methyl-2-thiophenecarboxylic acid (6.00 g, 42.20 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. was added dropwise n-butyllithium (2.5 M solution in hexanes, 40.5 mL, 101.2 mmol). The resulting reaction mixture was stirred at the same temperature for 1 h, and then bromine (3.00 mL, 58.38 mmol) was added dropwise. After 1 h at −78° C. the cooling bath was removed, and the mixture was allowed to warm to ambient temperature during 1 h, and then quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), and the combined aqueous layer was acidified at 0° C. with 37% aqueous hydrochloric acid to pH˜1-2. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford 5-bromo-3-methylthiophene-2-carboxylic acid as a beige solid (3.44 g, 37%): 1H NMR (300 MHz, CDCl3) δ 6.94 (s, 1H), 2.52 (s, 3H); MS (ES−) m/z 219.1 (M−1), 221.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.22 g (1.6 mmol) of 2-fluorobenzamide and 0.22 g (1.8 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-fluorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.3 g (1.6 mmol) of 2-chloro-4-fluoro-3-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.42 g (Yield 67%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(O)[C@@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 3C (10.234 g, 34 mmol), and trimethylsilyldiazomethane (2.0M in hexanes, 25 mL) in 3.5:1 benzene/methanol (232 mL) at room temperature was stirred at 0° C. for 1 hour, warmed to ambient temperature, stirred for 1 hour, quenched by the dropwise addition of acetic acid, concentrated to provide the desired product. MS (ESI) m/e 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 580 mg, 2.56 mmol) was dissolved in DMSO (20 mL). Sodium tert-butoxide (295 mg, 3.07 mmol) was added, followed by 1-(bromomethyl)-4-(methylsulfonyl)benzene (669 mg, 2.69 mmol) to give a brown solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (403 mg, 40%). ESI-MS m/z [M+H]+ calc'd for C17H19ClN4O3S, 395.09. found 395.4.