Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:13]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCC(C(=O)OCC)C(=O)OCC

Procedure:
A solution of sodium (0.46 g) in 10 of anhydrous ethanol is added with 3.35 ml of diethyl malonate in 3 ml of ethanol and successively with a solution of decylbromide (4.15 ml) in 3 ml of ethanol. The reaction mixture is refluxed for 4 hours, then the precipitate is filtered off and the filtrate is concentrated to dryness. The residue is redissolved in a saturated aqueous solution of sodium hydrogensulfate and it is extracted with ethyl acetate. The organic extract is dried over sodium sulfate and the solvent is evaporated off. The resulting residue is used as such in the successive reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(NN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCN(NC(=O)c3ccc(F)cc3)CC2)cc1
Yield: 80.5 %

Procedure:
N-[4-(4-Nitrobenzoyl)-1-piperazinyl]-4-fluorobenzamide (254 mg) was hydrogenated over 10% palladium on carbon (73 mg) in methanol (10 ml) at ambient temperature for 4 hours. The catalyst was filtered off over Celite pad and the filtrate was concentrated in vacuo to give crystals. The crystals were recrystallized from methanol, ethyl acetate and n-hexane to give N-[4-(4-aminobenzoyl)-1-piperazinyl]-4-fluorobenzamide (188 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCC(OO)=[O:16]>CCC(Cl)Cl>[O:16]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: CCC(=O)OO
Agent: CCC(Cl)Cl
Product: c1cc2c(cc1CC1CO1)OCO2

Procedure:
48.82 g (0.3 mol) of 5-(2-propenyl)-1,3-benzodioxole were reacted with 45 g (0.1 mol) of a 20% strength solution of perpropionic acid in dichloropropane at 30° C. as described in Example 1. After a reaction time of 6 hours, the peracid conversion was 96%. 5-(Oxiranylmethyl)-1,3-benzodioxole was formed with a selectivity of 68%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CCN(C(C)C)C(C)C>[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([C:2]2[S:3][C:4]([Br:7])=[CH:5][N:6]=2)[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 110 °C

Procedure:
A solution of 2,5-dibromothiazole (1.00 g, 4.12 mmol) in DIPEA (3.00 mL) was charged with tert-butyl 1-piperazinecarboxylate (0.767 g, 4.12 mmol) and heated to 110° C. for 3 h and then an additional 16 h at rt. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 0.5% EtOAc in CHCl3] resulting in the title compound as a light orange solid. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 3.37-3.44 (m, 4H), 3.51-3.59 (m, 4H), 7.08 (s, 1H). MS (ES+): m/z=348.09 (51/49) [MH+]. HPLC: tR=3.73 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:15]=[C:14]([Cl:19])[N:13]=[C:12]([Cl:11])[N:17]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N(N)c2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of p-methoxyphenylhydrazine (59 g.), 2,4,6-trichloropyrimidine (78.5 g.), and a solution of anhydrous sodium acetate (63 g.) in a mixture of water (260 ml.) and ethanol (1200 ml.) was shaken at room temperature for 2 hours. The crystalline precipitate which had formed was collected by filtration, washed with ethanol (50 ml.) and recrystallised from a mixture of chloroform (200 ml.) and ethanol (800 ml.) to give N-(p-methoxyphenyl)-N-(2,6-dichloropyrimidin-4-yl)hydrazine as a pale yellow solid, m.p. 156°-158° C. From the crystallisation mother liquors there was obtained, after chromatography on silica gel (300 g.) using a mixture containing equal parts by volume of ether and petroleum ether (b.p. 40° C.), N-(p-methoxyphenyl)-N-(4,6-dichloropyrimidin-2-ylhydrazine as a pale yellow solid, m.p. 113°-115° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[NH:19][CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH2:26][CH3:27])[CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CC2CCCc3c(C(=O)CCC4CCN(C(C)=O)CC4)ccc1c32
Yield: 75.8 %

Procedure:
A 10 ml suspension of 1.0 g of 3-(1-acetylpiperidin-4-yl)-1-(1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone, 2.3 g of ethyl iodide and 0.53 g of potassium carbonate in ethanol was stirred at 60° to 70° C. for 12 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, after which the reaction product was extracted with dichloromethane. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 0.82 g of 3-(1-acetylpiperidin-4-yl)-1-(1-ethyl-1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH2:11])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: O=S(=O)(O)O
Product: N#Cc1c(Br)nc(N)c([N+](=O)[O-])c1N

Procedure:
nitrating the corresponding 2-bromo-3-cyano-4,6-diamino pyridine with a mixture of nitric acid and sulphuric acid at -20° to +40° C to form the corresponding 2-bromo-3-cyano-4,6-diamino-5-nitro pyridine,
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14](O)=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3].B.CO.Cl>C1COCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][C@@H:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[N+:25]([O-:27])=[O:26])[CH2:17][S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1ccc(N[C@H](CCO)CSc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of Example 122E (206 mg, 0.50 mmol) and 1M borane in THF (20 mL) was stirred for 16 hours, treated sequentially with methanol (5.0 mL) and 1N HCl (2.0 mL), diluted with ethyl acetate (50 mL), washed with water (2 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/dichloromethane to provide the desired product. MS (ESI(+)) m/e 398 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[CH3:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([NH2:34])[C:30]=1[C:31](O)=[O:32]>CC#N>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([C:17]2[O:19][C:31](=[O:32])[C:30]3[C:25]([CH3:24])=[CH:26][CH:27]=[CH:28][C:29]=3[N:34]=2)=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: COCCOCCOCCOCCOc1ncccc1C(=O)O
Solvent: CC#N
Product: COCCOCCOCCOCCOc1ncccc1-c1nc2cccc(C)c2c(=O)o1
Temperature: 65 °C
Yield: 54 %

Procedure:
A solution of compound D (164.7 mg, 0.50 mmol) in CH3CN (2.0 mL) was treated with N,N′-carbonyldiimidazole (CDI, 81.1 mg, 0.50 mmol) at 65° C. under N2 for 1 h. 6-Methylanthranilic acid (75.6 mg, 0.50 mmol) was added at 25° C., and the mixture was heated at 65° C. overnight. Additional CDI (81.1 mg, 0.50 mmol) was added and the mixture was heated at 65° C. for 8 h. The crude mixture was purified by C18 reverse phase chromatography to provide compound 52 as colorless gum (120.0 mg, 54%). 1H-NMR (400 mHz, CDCl3) δ 8.29 (dd, 1H, J=5.2 Hz, J=2.0 Hz), 8.25 (dd, 1H, J=7.6 Hz, J=2.0 Hz), 7.66 (t, 1H, J=7.8 Hz), 7.50 (d, 1H, J=7.6 Hz), 7.31 (d, 1H, J=7.6 Hz), 7.01 (dd, 1H, J=7.4 Hz, J=5.0 Hz), 4.62 (m, 2H), 3.94 (m, 2H), 3.78 (m, 2H), 3.62 (m, 8H), 3.51 (m, 2H), 3.34 (s, 3H), 2.82 (s, 3H). ESMS: 445.0 [M+H]+, 467.0 [M+Na]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][C:34]1[O:38][N:37]=[C:36]([CH3:39])[CH:35]=1.N(C(OC)=O)=NC(OC)=O>O1CCCC1>[CH3:39][C:36]1[CH:35]=[C:34]([CH2:33][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[O:38][N:37]=1
Reactant: Cc1cc(CO)on1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CON2C(=O)c3ccccc3C2=O)on1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
8.17 g of N-hydroxyphthalimide and 23.9 g of triphenylphosphine were added to a solution of 5.15 g of 5-hydroxymethyl-3-methylisoxazole in 245 ml of tetrahydrofuran. A solution of 13.3 g of dimethyl azodicarboxylate in 20 ml of tetrahydrofuran was then added dropwise at room temperature under an atmosphere of nitrogen to the resulting solution. The mixture was then allowed to stand for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 7.21 g of N-(3-methylisoxazol-5-yl)methoxyphthalimide, melting at 129°-131° C.
Reaction SMILES: CO[C:3](=O)[NH:4][C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1>O1CCCC1>[CH2:17]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C@H:5]([NH:4][CH3:3])[CH2:6]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 19 h
Yield: 80 %

Procedure:
To a suspension of [(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-carbamic acid methyl ester (49.22 g, 142.7 mmol) in THF (520 mL) borane-tetrahydrofurane complex solution (1 M in tetrahydrofurane, 571 mL, 571 mmol) was added slowly over a period of 25 min. The reaction mixture was stirred for 19 h at 60° C. and then quenched with aqueous HCl (1N, 570 mL, dropwise over 60 min). The mixture was stirred for further 21 h at 60° C. After cooling to ambient temperature, tetrahydrofurane was distilled away and the residue was separated between tert-butylmethylether (1500 mL) and aqueous HCl (1N, 1000 mL). The aqueous layer was set to pH=10 with aqueous sodium carbonate (saturated, 2000 mL) and then extracted with tert-butylmethylether (twice 1500 mL). The organic layers were washed with brine (750 mL), combined and was dired over sodium sulfate. Concentration and filtration over silicagel (ethyl acetate:methanol, triethylamine=90:5:5) afforded the title compound (34.38, 80%) as a light yellow liquid. MS m/e: 301.4/303.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20](S(O)(=O)=O)=[CH:21][C:15]2=[N:14]1.[Na]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccc(S(=O)(=O)O)cc3n2)c(O)c(C(C)(C)C)c1
Agent: [Na]
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
2-(2-hydroxy-3-tert-butyl-5-methylphenyl)-2H-benzotriazole-5-sulfonic acid, sodium salt;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C#CC(C)(C)C)ccc1C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of methyl 2-methoxy-4-(3,3-dimethylbut-1-ynyl)benzoate (1.10 g, 0.00447 mol), MeOH (20 mL), and 2N aqueous NaOH solution (5 mL) was stirred at 65° C. overnight. After allowing to cool, the mixture was concentrated under vacuum. The residue was treated with water, and extracted with hexane. The aqueous layer was acidified with 1N HCl to pH 2-3, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2O4), filtered and concentrated under vacuum to give the product (870 mg, 84%) as a white solid. LC-MS: 3.22 min, 233.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cc1
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Yield: 92.9 %

Procedure:
Using the procedure described in Example 93, Part A, 4-bromoaniline (11.6 mmol) and 2-nitrobenzoyl chloride (12.8 mmol) yielded 3.46 g (93%) of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-chlorophenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 97 %

Procedure:
4-Chloro-3-nitrobenzoic acid (300 g) was dissolved in ethyl alcohol (1500 ml) and concentrated sulfuric acid (100 ml) was added with ice-cooling. The mixture was refluxed under heating for 7 hr. The reaction mixture was poured into ice-cold water and the precipitated crystals were collected by filtration to give the title compound (332 g, yield 97%).
Reaction SMILES: [NH2:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1>[C:39]([O:38][C:36]([NH:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25])=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 70 °C

Procedure:
A solution of ethyl 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (8.37 g, 22.42 mmol) and Et3N (6.25 mL, 44.8 mmol) in THF (100 mL) was added BOC2O (10.41 mL, 44.8 mmol), and then the reaction mixture was heated to 70° C. for 16 hrs. The reaction mixture was concentrated to afford ethyl 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate. LC/MS (M+H)+=474.3.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29](=[O:41])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:24][CH2:23]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:40][C:37]([F:38])([F:39])[C:33]1[CH:32]=[C:31]([CH2:30][C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([C:2]4[C:10]5[C:5]([NH:6][CH:7]=[N:8][C:9]=5[NH2:11])=[N:4][CH:3]=4)=[CH:28][CH:27]=3)[CH2:23][CH2:24]2)=[O:41])[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ncnc2[nH]cc(Br)c12
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc[nH]c2ncc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c1-2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (101 mg, 0.474 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (204 mg, 0.474 mmol), Pd2(dba)3 (8.68 mg, 0.00948 mmol) and K3PO4 (218 mg, 0.948 mmol) in 6 mL of dioxane and 2 mL of water in a microwave tube was degassed and backflushed with nitrogen 3×, followed by addition of tri-(t-butyl)phosphonium tetrafluoroborate (5.50 mg, 0.019 mmol). The mixture was degassed and backflushed with nitrogen 4×. The mixture was heated in an oil bath to 100° C. At 4 h, LCMS showed there was no starting material. The mixture was cooled to rt, EtOAc was added to the mixture. The top EtOAc layer was separated from the bottom layer carefully to avoid disturbance of the Pd residue. The EtOAc layer was rotavaped to dryness to give pale yellow solid. The solid was purified by flash column (Silica SF 15-24g cartridge), eluting with DCM-10% MeOH in DCM. The fractions with the product were combined and evaporated to dryness. The solid was triturated by MeOH, and the residue was filtered and dried to 5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-amine as an off-white solid. LC/MS [M+1]+438. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (t, J=8.34 Hz, 2H), 4.03 (s, 2H), 4.27 (t, J=8.46 Hz, 2H), 5.99 (s, 2H), 7.18 (d, J=2.27 Hz, 1H), 7.21-7.26 (m, 1H), 7.34 (s, 1H), 7.58-7.66 (m, 3H), 7.68 (s, 1H), 8.09-8.12 (m, 2H), 11.74 (s, 1H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:20][C:13]1[C:14]2[O:15][CH2:16][CH2:17][O:18][C:19]=2[C:10]([C:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)c2c1OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=CCC(=O)CC2)c2c1OCCO2
Yield: 93.9 %

Procedure:
To the mixture of Compound 2a (1.2 g, 3.6 mmol) obtained in Step A of Example 2 and p-toluenesulfonic acid monohydrate (1.2 mg, 0.0063 mmol) were added water (70 mL) and toluene (140 mL ), followed by refluxing for 4 hours. The mixture was allowed to cool, the mixture was extracted with toluene, and the extract was washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The mixture was dried over sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 16 (0.88 g, 94%) as a pale yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]2[CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:25]([O:24][C:22](=[O:23])[N:18]([CH:19]1[CH2:20][CH2:21]1)[CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(CC1CCN(C(=O)OCc2ccccc2)CC1)C1CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC1CCNCC1)C1CC1
Yield: 87 %

Procedure:
4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidine-1-carboxylic acid benzyl ester from Example E38.2 (3.67 g, 9.4 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (3 g) for 1 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (2.07 g, 87%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:15].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]1)[C:9]2=[O:15]
Reactant: O=c1[nH]ccc2c(Cl)c(Cl)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3c(Cl)c(Cl)ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Sodium hydride (95% dispersion in mineral oil, 0.026 g) was added to a room temperature suspension of the compound prepared in Example 75 (0.07 g) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for one hour and then tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.14 g) added to the system. The reaction mixture was heated at 80° C. overnight, then cooled to room temperature, diluted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution, water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:7) to obtain the title compound (0.05 g) having the following physical data.