Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[CH3:24][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22].[ClH:32]
Reactant: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC2CCNCC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-(6-Methyl-5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (590 mg; 1.75 mmol, prepared in accordance with Example 99) is dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) is added under stirring. After 30 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×10 mL). The product is then diluted in dioxane (6 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (477 mg; 1.75 mmol).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[CH:13]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])([CH2:15][CH3:16])[CH3:14]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([N:17]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:8]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: CCC(C)NC(C)CC
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)N(C(=O)c1ccc(C)c(Cl)c1)C(C)CC
Temperature: 25 °C

Procedure:
To these 17.9 g of the chloride of 3-chloro,4-methylbenzoic acid, dissolved in 60 ml of anhydrous benzene, were added 12.9 g of di-sec.butylamine dissolved in 15 ml of anhydrous C6H 6 and 12.3 g of triethylamine. The whole was then boiled to reflux temperature for 1 hour and was then left to cool down to room temperature. The reaction mass was then concentrated to dryness under reduced pressure. The residue was washed with acidulated H2O, with H2O and extracted with ethyl ether. The etheral extract was dried on anhydrous Na 2 SO4, filtered, and the solvent was then removed by reduced pressure. The oily residue was fractionally distilled at a pressure of 0.05 mm Hg. The fraction which passed over at 143°-144°C was collected. Thereby were obtained 26.5 g of 3-chloro,4-methyl-N,N-di-sec.butyl-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CN(C)C=O
Solvent: O
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
A mixture of 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (117 mg, 0.57 mmol) and TEA (115 mg, 1.14 mmol) in DMF (5 mL) was stirred at 120° C. under microwave heating for 1 h. Water was added to the mixture which was extracted with DCM. The combined organic layers were concentrated to give the desired compound as a colorless oil (170 mg, Yield 82%) and used directly in the next step. LCMS (m/z): 362.08, 364.08 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH3:14])[NH:12][C:11](=[O:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@H:9]1[CH2:10][C:11](=[O:15])[N:12]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=2)[C@H:13]1[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidin-2-one (5.00 g), 4-iodo-2-(trifluoromethyl)benzonitrile (6.80 g), cesium carbonate (10.65 g), tris(dibenzylideneacetone)dipalladium(0) (1.00 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.52 g), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 5.617 g, yield: 64.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (120 mg, 0.66 mmol) in 1.5 mL dioxane was added 3-chloroaniline (351 μL, 3.31 mmol). The mixture was heated in microwave 10 minutes at 120° C. The solid formed was isolated by filtration and air dried to give 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as orange solid. LCMS (M+1=273)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: O=C(Nc1ccc(F)cc1)c1ccccc1[N+](=O)[O-]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Yield: 80.7 %

Procedure:
To a stirred solution of N-(4-fluorophenyl)-2-nitrobenzamide (4.0 g, 15.4 mmol) in methanol (220 mL) and tetrahydrofuran (110 mL) was added nickel acetate tetrahydrate (7.7 g, 31 mmol). Sodium borohydride (2.3 g, 62 mmol) was added in small portions. After gas evolution had ceased, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and concentrated ammonium hydroxide, and the layers were separated. The organic phase was washed with concentrated ammonium hydroxide and saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 2.86 g (81%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[O:7][CH:8]([C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)[CH3:9].O.O.[Sn](Cl)Cl>CCOC(C)=O.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:17])=[C:6]([O:7][CH:8]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH3:9])[CH:16]=1
Reactant: Cc1cc(C(C)Oc2cc(F)ccc2[N+](=O)[O-])on1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)Oc2cc(F)ccc2N)on1

Procedure:
6.61 g (24.84 mmol) 5-[1-(5-fluoro-2-nitro-phenoxy)ethyl]-3-methyl-isoxazole and 24.66 g (109.30 mmol) tin(II)chloride dihydrate in EtOAc are stirred for 1 h at reflux. The mixture is diluted with 180 mL EtOAc and 180 mL aq. NaOH (4M). The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and brine, separated, dried and evaporated. The residue is purified by FC.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[C:23]([N+:29]([O-:31])=[O:30])=[N:24][C:25](Br)=[CH:26][CH:27]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[C:23]([N+:29]([O-:31])=[O:30])=[N:24][C:25]([N:13]2[CH2:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:11][C:12]2=[O:15])=[CH:26][CH:27]=1)[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC(=O)C1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(N2C[C@H](CO[Si](C)(C)C(C)(C)C)CC2=O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one (1.93 g, 8.43 mmol), [(6-bromo-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (synthesized with reference to WO2004/2992, 2.57 g, 8.43 mmol), potassium carbonate (2.33 g, 16.9 mmol), copper (I) iodide (803 mg, 4.21 mmol), N,N′-dimethylethylenediamine (0.449 ml, 4.21 mmol) and toluene (40 ml) was stirred at 100° C. for 8 hours under a stream of nitrogen gas. [(6-Bromo-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (1.29 g, 4.21 mmol) was added thereto and stirred overnight at 100° C. [(6-Bromo-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (1.29 g, 4.21 mmol), copper (I) iodide (803 mg, 4.21 mmol) and N,N′-dimethylethylenediamine (0.449 ml, 4.21 mmol) were further added thereto which was stirred at 100° C. for 24 hours. After cooling, ethyl acetate was added to the reaction solution to remove the insoluble material by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate), thereby obtaining 2.70 g (71%) of ({6-[(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxopyrrolidin-1-yl]-2-nitropyridin-3-yl}oxy)acetic acid ethyl ester in the form of a reddish brown gummy solid. The whole amount was dissolved in acetic acid (18 ml) to which reduced iron (999 mg, 17.9 mmol) was added and the mixture was stirred at 60° C. for 3 hours. After cooling, a mixed solution of chloroform-methanol (9:1) was added to remove the insoluble material by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 1.93 g (86%) of the title compound in the form of a yellow solid.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:32])[NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]([C:33](=[O:55])[C@@H:34]([NH:41][C:42](=[O:54])[C@@H:43]([N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH3:46])[CH3:44])[CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[N:45]([C@H:43]([C:42](=[O:54])[NH:41][C@@H:34]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:33]([N:20]1[CH2:19][C@@H:18]([NH2:17])[CH2:22][C@H:21]1[C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:55])[CH3:44])[CH3:46])([CH3:51])([CH3:52])[CH3:53]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
((3S,5S)-5-Benzylcarbamoyl-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-pyrrolidin-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester (100 mg, 0.13 mmol) was dissolved in DMF (0.9 mL) at room temperature and piperidine (0.1 mL) was added. The mixture was stirred at room temperature for 30 minutes, concentrated and the residue purified by silica gel chromatography to give the title compound as a white foam (71 mg, 52%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH2:34])=[O:33])[CH2:27][CH2:26]3)[N:7]2[N:8]=1
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 154 mg, 0.469 mmol) and 1-(piperidin-4-yl)urea hydrochloride (169 mg, 0.939 mmol) in NMP (1.5 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 2%). 1H NMR (DMSO-d6) δ: 10.97 (s, 1H), 8.33-8.52 (m, 2H), 7.07-7.37 (m, 4H), 6.08 (s, 2H), 5.41 (s, 2H), 4.24 (br. s., 2H), 3.65 (br. s., 2H), 3.16 (br. s., 2H), 2.35 (s, 3H), 1.89 (br. s., 2H), 1.50 (br. s., 4H). ESI-MS: m/z 435.0 (M+H)+.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]2([C:34]#[N:35])[CH2:27][CH2:26][N:25]([C@H:28]3[CH2:32][CH2:31][O:30][C@H:29]3[CH3:33])[CH2:24][CH2:23]2)=[N:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:14][C:16]1[CH:17]=[CH:18][C:19]([C:22]2([C:34]#[N:35])[CH2:27][CH2:26][N:25]([C@H:28]3[CH2:32][CH2:31][O:30][C@H:29]3[CH3:33])[CH2:24][CH2:23]2)=[N:20][CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1OCC[C@@H]1N1CCC(C#N)(c2ccc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1OCC[C@@H]1N1CCC(C#N)(c2ccc(N)cn2)CC1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
Benzophenonimine (570 mg) was added to a suspension of cis-4-(5-bromopyridin-2-yl)-1-(2-methyltetrahydrofuran-3-yl)piperidine-4-carbonitrile (1.05 g), palladium (II) acetate (17 mg), racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (47 mg) and sodium tert-butoxide (432 mg) in toluene (7.5 ml) and stirred at 120° C. for 7 hours. It was left stand and a mixture of concentrated hydrochloric acid (2 ml) and water (6 ml) was added at 60-80° C. and stirred at room temperature for 24 hours. The reaction solution was filtered through Celite and washed with water and ethyl acetate. The filtrate was washed with ethyl acetate, 1N aqueous solution of sodium hydroxide was added to the aqueous layer and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was washed with ethyl acetate and n-hexane to give the titled compound as a pale yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11]>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([Br:1])[CH:16]=2)=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)Nc1[nH]c2ccccc2c1C(N)=O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(Br)ccc2c1C(N)=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
N-Bromosuccinimide (4.8 g, 27 mmol) was added to a solution of 2-aminocarbonylaminoindole-3-carboxamide (Compound 2-10, 5.9 g, 27 mmol) in anhydrous N,N-dimethylformamide (180 mL) under ice-cooling, and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was poured into ice-water (400 mL) and the whole was extracted with ethyl acetate (500 mL). The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution (200 mL×2), 2 N sodium thiosulfate aqueous solution (200 mL×2), brine (150 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with chloroform (40 mL) and dried under reduced pressure to give the title compound (5.4 g) as a slightly brown solid (yield 67%).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH3:41][CH:42](O)[CH3:43].[ClH:45].O1CCOCC1>>[ClH:45].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH:42]([CH3:43])[CH3:41])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:39])([F:40])[F:38]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 45 °C
Reaction time: 4.5 h

Procedure:
640 mg (1.13 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoro ethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 2.00 mL (26.1 mmol) of 2-propyl alcohol were mixed, 11.3 mL (45.2 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 45° C. for 4.5 hours.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[N:3]1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1ccsc1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)c(-c1ccsc1)nn2C1CCCCO1
Yield: 57.9 %

Procedure:
The title compound (0.233 g, 38% yield) was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.30 mmol), in ethylene glycol dimethyl ether (10 mL), 3-thiophene boronic acid (0.251 g, 1.96 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.150 g, 0.130 mmol), and potassium phosphate (1.38 g, 6.5 mmol): ES-MS (m/z) 310 [M+1]+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:20][C:19]([F:21])([F:22])[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-trifluoromethyl-benzene (0.287 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.135 g, 93%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.86 (s, 2H), 7.39-7.62 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.Br[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[N:8]([CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reactant: Cn1c(=O)[nH]c2c(OCC3CCC3)c(Br)ccc21
Product: Cn1c(=O)n(CCC2CCN(C(=O)OC(C)(C)C)CC2)c2c(OCC3CCC3)c(Br)ccc21

Procedure:
This compound was synthesized according to the procedure of Example 44, Step 2, using 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate as the starting materials. LCMS calculated for C20H29BrN3O2 ([M-Boc+H]+H)+: m/z=422.2, 424.2. found: 422.0, 424.0.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.P(Cl)(Cl)([Cl:16])=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([Cl:16])=[N:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc2c(Br)cnc(Cl)c2c1
Temperature: 66 °C
Reaction time: 3 h

Procedure:
4-bromo-7-chloroisoquinoline 2-oxide (3-7) (1.2 g, 4.64 mmol, 1.0 equiv.) was dissolved in anhydrous CHCl3 (20 mL) and treated dropwise with phosphorus oxychloride (0.649 mL, 6.96 mmol, 1.5 equiv.). The reaction mixture was refluxed at 66° C. LCMS after 3 hours showed only product. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3, and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane, and filtered to afford the product 3-8. LRMS m/z (M+H) 277.9 found, 277.9 required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.OC1C=CC=C2C=1N=CC=C2.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[N:24]1([C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([C:9]([F:10])([F:12])[F:11])[CH:5]=2)[NH2:1])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 3-Amino-5-bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol). CuI (0.476 g, 0.025 mol), imidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) in 17 mL of DMSO (degassed with argon for −10 min) was heated at 120° C. under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product.