Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:5]2=[O:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[C:5]2=[O:23])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of benzyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (1.0 g, 3.22 mmol) in pyridine (8 ml) cooled to 0° C., methanesulfonyl chloride (0.377 ml, 4.83 mmol) was added drop wise, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue was partitioned between 2N HCl and DCM; the aqueous phase was extracted with DCM and the combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude was triturated with Et2O (15 ml) to give benzyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1.1 g, 2.83 mmol, 88% yield, MS/ESI+ 388.8 [MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[Na+]>CN(C)C=O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.06 Grams of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 1.8 g of anhydrous pyridine were mixed with 50 ml of dimethylformamide. Then the mixture was cooled with ice and 2.5 g of methanesulfonyl chloride was added to the mixture and stirred at a room temperature for 3 hours. The reaction mixture was poured into 100 ml of a saturated sodium chloride solution and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure to obtain a residue. The residue was crystallized by adding 80 ml of hexane to obtain crude crystals. The crude materials were collected by filtration and were recrystallized from ethanol to obtain 4.5 g of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32]C)=[O:31].[I-].[Li+].C(OCC)(=O)C.Cl>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (28 g) in 2,4,6-collidine (100 ml) was heated to 65° C. and lithium iodide (50 g) was added. After 3 days the solution was added to ethyl acetate and dilute hydrochloric acid. The organic layer was dried and evaporated to afford (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([Cl:19])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1cc(N)ccc1Cl
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1Cl

Procedure:
(2-amino-5-chloro-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xcc) was prepared by reacting 2-chlorobenzaldehyde with 0.019 moles of 3-methoxy-4-chloro aniline in a manner analogous to Example 1. MH+/Z=296.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 60 °C
Yield: 58 %

Procedure:
10.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 8.3 g 4-chloro-6-methoxy-pyrimidine and 16 mL triethylamine in 40 mL DMF. The reaction was stirred over night at 60° C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified chromatography on silica gel (petrolether/ethyl acetate: 8/2) to yield 9.8 g of the desired compound.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7](=[O:15])[O:6][C:5]=1[NH:16][C@@H:17]([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)(=[O:3])[CH3:2].[OH-:28].[Na+]>O1CCCC1.CO>[CH:25]1([C@H:17]([NH:16][C:5]([CH:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7]([OH:6])=[O:15])[C:1](=[O:3])[CH3:2])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:27][CH2:26]1
Reactant: [OH-]
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CC2)oc(=O)c2c(F)cccc12
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CC1)c1cccc(F)c1C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-Acetyl-3-{[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amino}-8-fluoro-2-benzopyran-1-one (14.30 g, 38.72 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) and placed on an ice/water bath with stirring. NaOH (1 M in H2O, 100 ml) was added and stirring continued for 1 hour. The cold bath removed and the mixture was allowed to warm to r.t. (20° C.) during 1 hour. The reaction mixture was poured into ice-water mixture (200 g+200 ml), followed by slow addition of 2 M aq. HCl (200 mL) and extracted with ethyl acetate (200 mL), washed with sat. aq. NaCl, dried (Na2SO4), filtered and evaporated to give the title compound (14.65 g, yield 97.7%) as a pale brown foam. The crude product was used in the next step without further purification. LC-MS (m/z) 388.3 (MH+); tR=1.2. 1H NMR (500 MHz, DMSO-d6): a mixture of tautomers and diastereoisomers.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH3:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, light yellow solid (73 mg, 88%), MS (ISP) m/z=334.6 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]CCCC.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=1)=O>O.C(OCC)(=O)C.CN(C)C=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:37]/[C:39]2[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: CCCC[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 4-nitrobenzyl bromide (6.35 g), triphenylphosphine (7.71 g) and N,N-dimethylformamide (50 ml) was stirred for 5 hours at room temperature. To the mixture were added potassium butoxide (3.96 g), and then N-(4-formyl-1,3-thiazol-2-yl)acetamide (5.0 g) prepared in a similar manner according to Step 4 of Production Example 1, and the mixture was stirred for 13 hours at the same temperature. The reaction mixture was poured into ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with 30% ethyl acetate/diisopropyl ether to give N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (7.8 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:41]=3)=[C:18]([O:42][CH3:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:44])=[CH:17][C:18]=4[O:42][CH3:43])=[N:41][C:27]2=3)[CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 820.6 %

Procedure:
A mixture of 0.095 g (0.22 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.078 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 0.078 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.055 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([NH:17]N)[CH:9]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]2[C:9]=1[C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=1[NH:17]2
Reactant: NNc1cc(-c2ccccc2F)ccc1C(=O)O
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Step 4 A solution of 2′-fluoro-3-hydrazinylbiphenyl-4-carboxylic acid (0.306 g, 1.24 mmol) and cyclohexanone (0.183 g, 1.86 mmol) in acetic acid (6.2 mL) was heated at reflux under nitrogen for 2 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and 1 M hydrochloric acid. The organic layer was washed with brine, dried and concentrated. The residue was triturated with EtOAc and DCM to give 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.132 g) as a white solid. The filtrate was purified by column chromatography (eluting with a gradient from hexane to 50:50 EtOAc-hexane) to give additional product (0.029 g, 41% total). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br s, 1 H), 10.79 (s, 1 H), 7.68 (d, J=7.15, 1 H), 7.42-7.51 (m, 1 H), 7.24-7.34 (m, 3 H), 6.87 (d, J=7.15, 1 H), 2.67-2.82 (m, 2 H), 1.89-2.10 (m, 2 H), 1.65-1.81 (m, 2 H), 1.44-1.63 (m, 2 H). Mass spectrum m/z 310.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8](Cl)=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([CH3:15])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77.4 %

Procedure:
To a solution of 5-tert-butyl-2-chloro-3-nitro-pyridine (554 mg, 2.58 mmol) dissolved in 10% aqueous dioxane (5.0 mL) was added potassium carbonate (1.07 g, 7.74 mmol), trimethylboroxine (395 mL, 2.84 mmol), and lastly tetrakis-(triphenylphosphine)palladium (149 mg, 0.129 mmol). The solution was heated in a sealed tube to 100° C. for 18 h, cooled to room temperature and diluted with ether. The organic layer was washed twice with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica-gel chromatography (10% ethyl acetate in hexane) provided 5-tert-butyl-2-methyl-3-nitro-pyridine (388 mg, 75%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:3][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N3CCOCC3)cc(C(C)(C)S(C)(=O)=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
Tert-butyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate (2.6 g, 5.46 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)ccc21

Procedure:
Title compound was prepared from 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (63 mg, 58%). LCMS: 501.11 (M+H), HPLC purity 99%, MP 105-109, 1H-NMR (CDCl3, 400 MHz) δ 12.01 (s, 1H), 10.27 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 8.05 (s, 1H), 7.57-7.44 (m, 4H), 7.15 (d, J=8.6 Hz, 1H), 3.35 (s, 3H), 3.14 (s, 3H), 2.34 (t, J=7.0 Hz, 2H), 2.07-2.03 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31](=[O:43])[N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:34][CH2:33]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31](=[O:43])[N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([F:40])([F:41])[F:42])[CH2:34][CH2:33]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75.9 mg, 103 μmol) in dichloromethane (5 mL) under Ar, trifluoroacetic acid (744 mg, 0.50 mL, 6.52 mmol) was added at 25° C. After 96 h, the reaction was concentrated in vacuo and stirred in a mixture of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) at 25° C. After 2.5 h, the material was concentrated and dried in vacuo (200 mTorr, 25° C.) to give a yellow solid. The solid was purified by chromatography (silica, 12 g Analogix column, 10-100% ethyl acetate in hexanes, gradient over 1 h) to give a yellow oil. The oil was dissolved in ethanol (4.5 mL, 200 proof) and cooled to 4° C. The precipitated solid was isolated by filtration and dried in vacuo (100 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (36.2 mg, 54.1 μmol, 53%) as a yellow solid. MS (M)'=609; 1H NMR (DMSO-d6) δ: 12.84 (d, J=3.0 Hz, 1H), 9.03 (s, 1H), 8.40 (d, J=3.0 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.39 (dd, J=2.3, 9.0 Hz, 1H), 7.20 (t, J=74.5 Hz, 1H), 5.66 (s, 2H), 3.64 (br. s, 2H), 3.47 (br. s, 2H), 3.29 (q, J=10.3 Hz, 2H), 2.77 (br. s, 2H), 2.64 (br. s, 2H), 1.51 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:6])([CH3:5])[CH3:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:3]([O:7][C:8](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)n1cccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium hydride (313 mg, 7.83 mmol, 60% purity in mineral oil) was added in one portion to a stirred, ice/water-cooled solution of pyrrol-1-yl-carbamic acid tert-butyl ester (951 mg, 5.22 mmol) and benzyl bromide (745 μL, 6.26 mmol) in DMF (20 mL); the mixture was stirred in the cold bath for 30 min, at which time TLC showed complete disappearance of starting material; then poured into diluted, cold ammonium chloride solution to quench the reaction, followed by extraction with EtOAc, then washed with water, and brine; then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was silica gel column purified to give desired product (1.376 g) as a clear oil. ESI (m/z): 273 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][OH:13].N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:20]([O:13][CH2:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A stirred solution of 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, 0.283 mole) and 25 ml of pyridine in 350 ml of toluene was warmed to 70°. During a ten minute period, acetyl chloride (22.2 g, 0.283 mole) was added to the reaction mixture. The reaction mixture was heated at 85° for 21/2 hours, then poured over 300 g of ice, and 100 ml of a 4 N hydrochloric acid solution was added thereto. The organic phase was separated and washed with 100 ml of aqueous 2 N hydrochloric acid, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give (2,6-dimethyl-3-nitrophenyl)methyl acetate (47.5 g) as an oil.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH2:2])=[CH:14][N:13]=1
Reactant: C=C[B-](F)(F)F
Reactant: Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc(C)nc1
Temperature: 77.5 °C

Procedure:
Water (10 mL) was added to a mixture of potassium vinyltrifluoroborate (6.35 g, 47.4 mmol, Aldrich), 5-bromo-2-methylpyridine (8.00 g, 46.5 mmol,), triphenylphosphine (0.732 g, 2.79 mmol) and Cs2CO3 (45.5 g, 140 mmol) in a 500 mL round-bottom flask with stir bar. The flask was evacuated and purged with nitrogen (3 cycles), and the mixture was then heated under nitrogen at 75-80° C. for 19 hours, and then cooled to room temperature. The mixture was diluted with water (100 mL) and hexanes (50 mL), and the aqueous layer was drawn off and extracted with ether-hexanes (4:1, 50 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4 and distilled at atmospheric pressure to a volume of ca. 10 mL. The residue was distilled under vacuum (90-100° C./20 Torr) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.51 (s, 3H) 5.35 (d, J=11.1 Hz, 1H) 5.86 (d, J=17.8 Hz, 1H) 6.74 (dd, J=17.8, 11.1 Hz, 1H) 7.27 (d, J=7.9 Hz, 1H) 7.84 (dd, J=8.3, 2.4 Hz, 1H) 8.40 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[CH3:12]>C(O)CC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[N:4]=1
Reactant: CC(=O)CBr
Reactant: Nc1ccc(Cl)nn1
Solvent: CCCO
Product: Cc1cn2nc(Cl)ccc2n1
Yield: 48.8 %

Procedure:
A solution of 13.0 g of 3-amino-6-chloropyridazine, 15.2 g of bromoacetone in 200 ml of propanol is heated under reflux for 3 hours. After cooling, the precipitated crystals are collected by filtration and dissolved in 100 ml of water. The solution is neutralized with potassium carbonate and the precipitated crystals are collected by filtration. Upon recrystallization from ethanol, it affords 8.2 g of the title compound having mp. 131° C.