Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33].C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.CN1C=CN=C1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[C:3]=1[C:4]([NH:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33])=[O:6]
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Reactant: NN1CCOC1=O
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cn1ccnc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)NN2CCOC2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.24 Grams of 2-chloro-6-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid was dissolved in 20 ml of N,N-dimethylformamide. To the solution were added 1.20 g of 3-amino-2-oxazolidinone sulfate, 0.67 g of triethylamine, 1.82 g of 2,4,6-triisopropylbenzenesulfonyl chloride and 0.98 g of 1-methylimidazole. The resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer separated therefrom was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed from the dried layer under reduced pressure to obtain a residue. Purifying the residue with thin layer chromatography (silica gel, chloroform/methanol: 9/1 by volume) gave 0.2 g of 3-{2-chloro-6-(4,6-dimethoxypyrimidin-2-yl)oxybenzoyl}amino-2-oxazolidinone (present compound (172)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([C:20]1[S:24][C:23]([S:25]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])=[O:26])=[C:22](B(O)O)[CH:21]=1)[CH:17]([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[N:10]1([CH2:9][C:8]([C:4]2[CH:3]=[C:2]([C:22]3[CH:21]=[C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])[S:24][C:23]=3[S:25]([NH:28][C:29]([CH3:31])([CH3:30])[CH3:32])(=[O:27])=[O:26])[CH:7]=[CH:6][CH:5]=2)=[O:15])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: O=C(Cn1ccnc1)c1cccc(Br)c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(C(=O)Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-imidazol-1-ylethanone (102 mg, 0.385 mmol; see step (a)) in toluene (10 mL) and ethanol (1 mL) was added 5-isobutyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (209 mg, 0.654 mmol; see Example 1(c)), Pd(PPh3)4 (26.7 mg, 0.023 mmol) and Na2CO3 (769 μL, 1.54 mmol, 2.0 M aq), and the reaction mixture was stirred for 4 h at 80° C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic phase was dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound as a colourless syrup in 95% yield (168 mg, 0.366 mmol).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(Cl)ccc1Cl
Yield: 69 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.012 g) was reacted with 2,5-dichlorobenzyl bromide as in General Procedure 1 to give the title compound as a brown solid (69% yield). M.p.>200° C., LCMS: m/z=434.36 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.18 (2H, s), 5.07 (2H, s), 4.18 (2H, s), 7.14 (1H, d, J=1.8 Hz), 7.15 (1H, d, J=2.3 Hz), 7.40 (1H, dd, J=8.6, 2.5 Hz), 7.56 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=1.8 Hz).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:47]3=[O:50])=CC=2)=CC=1.COC1C=CC=CC=1C(Cl)=O>>[CH3:47][O:50][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COc1ccccc1C(=O)Cl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4OC)cc3)cc2C1=O
Yield: 90 %

Procedure:
The compound of example 159 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-methoxy benzoyl chloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[NH2:31].CCN(C(C)C)C(C)C>>[CH3:27][O:26][CH2:25][CH2:24][N:11]([CH2:10][CH2:9][O:8][CH3:7])[C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:18][N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[N:29]=2)=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1ccc(-c2nc(-c3ccccc3OC)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 31 (149 mg; 0.5 mmol; 1 eq.), Intermediate 1 (83 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) followed by crystallisation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: N[C:2]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(O)C.N([O-])=O.[Na+]>Cl.O>[Br:18][C:16]1[CH:15]=[C:14]2[C:3]([C:4](=[O:5])[NH:6][N:7]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:2][CH:17]=1
Reactant: Nc1cc(Br)ccc1C(=O)NNc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Temperature: 76 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 2-amino-4-bromo-N′-phenylbenzohydrazide (4 g, 13.07 mmol, 1.00 equiv) in 1N HCl:Ethanol=1:1 (40 mL). The resulting solution was heated to 76° C. The solid dissolved to yield red solution. To the resulting mixture was then added a solution of NaNO2 (2.7 g, 39.13 mmol, 3.00 equiv) in water (5 mL) dropwise with stirring at 76° C. The resulting solution was stirred for 1 h at 76° C. in an oil bath. The resulting mixture was cooled to 20° C. with a water bath. The solids were collected by filtration, washed with water (2×40 mL), then dried in an oven under reduced pressure to yield 6-bromo-1-phenyl-1,2-dihydroindazol-3-one as a red solid. MS: 288 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16]([NH:19][C@H:20]([C:23]([O:25]C)=[O:24])[CH2:21][OH:22])(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16]([NH:19][C@H:20]([C:23]([OH:25])=[O:24])[CH2:21][OH:22])(=[O:17])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N[C@@H](CO)C(=O)O)s2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl N-({5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-2-thienyl}sulfonyl)serinate (15) (48 mg; 0.11 mmol; 1 eq), is dissolved in THF (2 ml). The resulting solution is cooled down to 0° C. and sodium hydroxide (5M) (0.3 ml; 14 mmol; 12.5 eq) is added slowly. The reaction mixture is stirred at room temperature for 30 minutes, then neutralized with HCl (1M). The solvents are evaporated to dryness and the expected compound is extracted with EtOAc (3 times) and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in ACN, affording after filtration, Compound (16) as a white solid (5 mg; 10%).
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[I:13]>C(Cl)Cl>[I:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: COC1(C)OC2CCC2O1
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1I
Yield: 76.5 %

Procedure:
73.4 g (0.51 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 102.0 g (0.51 mol) of trimethyliodosilane in 300 ml of methylene chloride are heated to the reflux for 15 hours. Working up by distillation gives 93.6 g (82%) of trans-1-iodo-2-acetoxy-cyclobutane. Boiling point12 94°-95°, nD20 1.5203.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C.[N:15]([O-])=O.[Na+]>O>[C:1]1([N:7]=[N+:8]=[N-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylhydrazine (6.7 g, 62 mmol) was added dropwise to a cold (0° C.) solution of concentrated hydrochloric acid (60 ml) over a period of 10 minutes. Diethyl ether (20 ml) was then added, followed by the dropwise addition of a solution of sodium nitrite (5 g, 72 mmol) in water (6 ml), keeping the temperature below 5° C. The reaction was then stirred at 0° C. for 1 hour and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (2×50 ml), saturated brine (50 ml), dried (MgSO4) and carefully evaporated in vacuo to give the crude title compound as a red oil (3.3 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[CH:24]=[N:25][N:26]([CH3:27])[C:22]=1[OH:21])=[O:5]
Reactant: Cn1nccc1O
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C)c3O)c2Cl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
At 0–5° C., a solution of 6.7 g (20 mmol) of 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 80 ml of dimethoxyethane was added dropwise to a solution of 2.0 g (20 mmol) of 5-hydroxy-1-methylpyrazole and 3.3 g (24 mmol) of potassium carbonate in 30 ml of anhydrous dimethoxyethane. After 12 hours of stirring at room temperature, a further 8.2 g (60 mmol) of potassium carbonate were added, and the batch was refluxed for six hours. After cooling, the reaction mixture was stirred into 1 l of water and extracted with methylene chloride. The aqueous phase was then adjusted to pH 4 using 10% strength hydrochloric acid and extracted repeatedly with methylene chloride, with readjustment of the pH. The organic phase was dried and the solvent removed, giving 5.3 g (13 mmol, 67%) of the desired compound.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][CH2:11][C:12]([F:16])([F:15])[CH2:13][OH:14])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].CC(C)=O.C1CCCCC1>ClCCl>[C:4]1(=[O:27])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:10][CH2:11][C:12]([F:16])([F:15])[CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)CO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phthalimido-4-p-toluenesulfonyl-7,7-difluoro-8-hydroxy-4-aza-octane (56.0 g, 120 mmoles) and dry pyridine (50 mL) in dry dichloromethane (400 mL), a solution of methanesulfonylchloride (14.4 g, 1.05 equivalents) in dichloromethane is added slowly at room temperature. After stirring overnight at room temperature, the mixture is washed with 1N HCl (500 mL), 10% aqueous NaHSO3 (250 mL), and water (250 mL). Drying (Na2SO4) and evaporation of the solvent yields an oil which solidifies under oil pump vacuum. Digestion with an acetone/cyclo-hexane mixture gives colorless crystals of 1-phthalimido-4-p-toluenesulfonyl-7,7-difluoro-8-methanesulfonyloxy-4-aza-octane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][CH:10]=O)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1.CS(C1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=2[N:25]=1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]2[N:21]=[CH:22][C:23]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=3[N:25]=2)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1nc(S(C)(=O)=O)ccc1NC=O
Product: COc1nc(S(C)(=O)=O)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 6 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)formamide (Preparation 73) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with DCM and dried under vacuum to give the title compound (3 mg, 6%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[NH2:13][C:14]1[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][C:17]([Br:24])=[CH:16][N:15]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[NH2:13][C:14]1[C:19]([S:20]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)(=[O:22])=[O:21])=[CH:18][C:17]([Br:24])=[CH:16][N:15]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(Br)cc1S(=O)(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of (R)-pyrrolidin-3-ol (32 mg, 0.37 mmol) and potassium carbonate (102 mg, 0.74 mmol) in dioxane (2 mL) and water (400 uL) was added 2-amino-5-bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol, prepared according to the methods in WO2008144463). The reaction mixture was stirred for 2 h at rt. Saturated sodium bicarbonate was then added, and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide (R)-1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ol (87.3 mg, 0.27 mmol, 73% yield) as a white solid. 1H NMR (400 MHz, DMSO-D6-d6) δ 8.31 (d, 1H), 7.92 (d, 1H), 6.85 (br s, 2H), 5.02 (br s, 1H), 4.23 (dt, 1H), 3.38-3.25 (m, 3H), 3.14-3.06 (m, 1H), 1.92-1.81 (m, 1H), 1.77-1.67 (m, 1H); MS (EI) for C9H12BrN3O3S: 322, 324 (Br isotopes, MH+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[C:15]1[N:23]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1)=[NH:4].[C:34](OC(=O)C)(=O)[CH3:35]>C1(C)C=CC=CC=1>[CH3:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]3[N:4]=[C:34]([CH3:35])[O:1][N:2]=3)=[CH:13][CH:12]=2)[C:8]([C:15]2[N:23]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:9]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C(=N)NO)cc34)cc3cccnc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5noc(C)n5)cc34)cc3cccnc32)cc1
Yield: 43.4 %

Procedure:
To a suspension of N-hydroxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carboxamidine [0.7 g, Reference Example 26] in toluene (30 mL) at ambient temperature under nitrogen was added acetic anhydride (0.467 g). The reaction mixture was heated at reflux for 4.5 hours then filtered. The filtrate was evaporated to give the title compound (0.32 g) as a dark red oil which was used immediately without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([N:31]=[N+:32]=[N-:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4.70 g (10.8 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (WO 03/099771; Ex. 163) in 50 ml DMF, 1.4 g (21.6 mMol) NaN3 are added at rt. Then the mixture is stirred for 3 h at 70° C., cooled to rt and pored into water and extracted tree times with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: m.p.: 167-168° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:14](=[O:15])[CH2:13][Cl:12]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)O)c1NC(=O)CCl
Yield: 73.4 %

Procedure:
3-Methylanthranilic acid 10 g (0.07 mol) was dissolved in dried benzene 100 ml. To this solution, chloroacetylchloride 5.81 ml (0.07 mol) was added dropwise at room temperature and heated under reflux for two hours. After cooling, deposited crystals were collected by filtration and recrystallized from benzene-toluene to obtain 3-methyl-N(chloroacetyl)anthranilic acid 11.7 g (yield: 79%).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8](OC(=O)C)([CH3:11])([CH3:10])[CH3:9].CS(O)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH3:31])[CH:30]=1)[NH:27][N:26]=[CH:25]2>O>[Br:21][C:22]1[CH:30]=[C:29]([CH3:31])[C:28]2[C:24](=[CH:25][N:26]([C:8]([CH3:9])([CH3:10])[CH3:11])[N:27]=2)[CH:23]=1
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Temperature: 80 °C
Reaction time: 28 h

Procedure:
Toluene (150 mL), acetic acid tert-butyl ester (360 mL), and methanesulfonic acid (22 mL) were added to 5-bromo-7-methyl-1H-indazole (35.9 g), and the reaction solution was stirred at 80° C. for 28 hours. The reaction solution was cooled to room temperature, water (500 mL) was added, and extracted with toluene (500 mL) and 200 mL toluene. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. Hexane was added to the resultant residue and the insolubles were separated by filtration. The solvent was evaporated from the filtrate under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole as a light red oily substance.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:8]([CH2:25][CH2:26][CH3:27])[C:9](=[O:11])[CH:10]=1
Reactant: CCCBr
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and bromopropane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (54%), m.p. (EtOAc/hexanes) 147-150° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.29 (s, 1H), 8.50 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.46 (d, J=1.3 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.85 (t, J=7.3 Hz, 2H), 1.62 (sextet, J=7.3 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 0.85 (t, J=7.4 Hz, 3H). Anal. Calcd for C17H18FIN2O3: C, 46.0; H, 4.1; N, 6.3. Found: C, 45.8; H, 3.9; N, 6.0.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.9 %

Procedure:
4 M NaOH (100 mL, 0.4 mol) was added to a solution of 5-benzyloxyindole (20 g, 0.09 mol), tetrabutylammonium hydrogen sulfate (6.1 g, 0.018 mol) and benzenesulfonyl chloride (27 g, 0.15 mol) in DCM (500 mL) The mixture was stirred at room temperature for 6 hours and additional benzenesulfonyl chloride (4.1 g, 0.023 mol) was added. The mixture was stirred overnight and diluted with water and DCM. The mixture was transferred to a separation funnel and extracted with DCM (2×), dried (MgSO4) and evaporated. The crude product was suspended in diethylether (1000 mL) and filtered. The solid cake was washed with diethylether (2×) and discarded. The filtrate was evaporated to approximate 100 mL (precipitation of white solid) and filtered. The white crystals were washed with cold diethylether (2×) and dried in vacuo to give 15 g of a white solid. MS m/z 364 [M+H]+