Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](Cl)=[O:38])[CH:34]=[N:33]1>ClCCl>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[O:38])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cnn(C)c2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (53.8 mg, 0.144 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.10 mL, 1.2 mmol) and 1-methyl-1H-pyrazole-4-carbonyl chloride (27.7 mg, 0.192 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL dichloromethane, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.1 mg (61%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-1-methyl-1H-pyrazole-4-carboxamide. LCMS (ESI): RT (min)=4.307, M+H=426.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.80 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=4.9 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.70 (dd, J=10.3, 4.6 Hz, 3H), 7.30 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.25 (s, 3H), 2.19-1.98 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:22][C:23]([C:25]2[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:10]=[CH:11][C:12]=1[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:33](Cl)(=[O:35])[CH3:34].Cl>O1CCCC1>[C:33]([N:22]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:23]([C:25]1[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=1[CH3:30])=[O:24])(=[O:35])[CH3:34]
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)c1c(C)nn(C)c1C)c1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Sodium hydride (38 mg, 60%, 0.96 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (300 mg, 0.64 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of acetyl chloride (75 mg, 0.96 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (90 mg).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:40][C:29]1[CH:28]=[C:27]([S:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)(=[O:25])=[O:26])[CH:39]=[CH:38][C:30]=1[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Yield: 58.6 %

Procedure:
To a solution of N-pentyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (70.6 mg, 0.23 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (101 mg, 0.35 mmol) and triethylamine (96 μL, 0.69 mmol). The resultant mixture was stirred for 24 h at room temperature. The reaction mixture was extracted with CH2Cl2 (15 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:49–1:19 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (76 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([SH:12])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([S:12][CH3:14])=[N:8][C:7]=1[OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(S)nc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc(SC)nc1O
Reaction time: 1 h

Procedure:
To a 0° C. solution of 29.0 g (144.1 mmol) of 5-hydroxy-3-mercapto-1,2,4-triazine-6-carboxylic acid ethyl ester in 75 mL of DMF was added 14.4 g (144.1 mmol) of potassium carbonate. The reaction mixture was stirred for 1 hour, and 24.2 mL (389.2 mmol) of methyl iodide was added as fast as the effervescence would allow. The ice bath was removed, and the reaction was covered with a nitrogen filled balloon and stirred at room temperature overnight.
Reaction SMILES: C(O)C.C([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24]C(=O)C)[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)(=O)C>O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1cccc(C#CC=Cc2cccc(NC(C)=O)c2)c1
Solvent: CCO
Solvent: O
Product: Nc1cccc(C#CC=Cc2cccc(N)c2)c1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To 50 ml of a 28% aqueous ethanol solution was added 2.6 g (0.0084 mole) of 1,4-bis-(3-acetamidophenyl)-buta-1-ene-3-yne and the mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into 300 ml of distilled water and extracted with three 100 ml portions of methylene chloride. Removal of the methylene chloride under reduced pressure provided a light yellow material. Recrystallization of the material from a one-to-one mixture of benzene/hexane gave 1 g (50% yield) of product (m.p. 105°-106° C.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][CH:15]([NH2:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:17][CH:15]([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), propan-2-amine (0.15 mL, 1.5 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue was suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined were dried with sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=2:1) to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 62%). 1H NMR (300 MHz, DMSO): δ 12.95 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.59-7.56 (m, 1H), 4.13-4.06 (m, 1H), 1.24-1.20 (m, 6H). LCMS: (M+H)+=283/285.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(c2ccccc2)C(=O)Nc2ccc(Br)cc21
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 5-Bromo-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (602 mg, 2 mmol), compound 3,5-dimethylisoxazole-4-boronic acid (564 mg, 4 mmol), Pd(PPh3)4 (440 mg, 0.4 mmol) and Cs2CO3 (1.624 g, 5 mmol) in dioxane (10 mL) and H2O (5 mL) is stirred at 80° C. under nitrogen for 20 hours. The mixture is poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate:petroleum ether=1:2) to give the desired compound.
Reaction SMILES: C(S(O)(=O)=O)(F)(F)F.[OH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C1C(=O)N([I:25])C(=O)C1>CC#N>[OH:9][C:10]1[CH:17]=[CH:16][C:15]([I:25])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccccc1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81626.9 %

Procedure:
CF3SO3H (40 mL) was added dropwise to a solution of 2-hydroxy-benzonitrile (47.6 g, 0.400 mmol) in CH3CN (500 mL) at 0° C., and then stirred at 0° C. for 20 min, then NIS (108 g, 0.48 mmol) was added. The reaction mixture was stirred at rt overnight, concentrated, then diluted with H2O (300 mL) and extracted with EA (300 mL×3). The combined organic parts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification via FC (PE/EtOAc=5/1) afforded the title compound as a white solid (80 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([NH:12][CH2:13][C:14]#[CH:15])(=[O:11])[CH3:10]>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][NH:12][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: C#CCNC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(=O)NCC#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
A mixture of 2,5-dibromopyridine (1-1) (1.19 g), N-acetyl-propargylamine (733 mg), CuI (10 mg), and Pd(PPh3)2Cl2 (73 mg) in diisopropylamine (20 mL) was stirred at ambient temperature under nitrogen atmosphere over 3 days. The mixture was diluted with ethyl acetate (50 mL). The solid was filtered and washed with ethyl acetate. The filtrate and wash were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate as eluant to give crystalline 1-2 (1.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:26][CH2:27][CH2:28][OH:29])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:16])([F:18])[F:17]
Reactant: OCCCBr
Reactant: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(OCCCO)cc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a solution of 6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (10 g, 36.23 mmol) in 150 mL DMF was added cesium carbonate (24.8 g, 76.11 mmol) followed by 3-bromo-1-propanol (7.6 g, 54.3 mmol) and the mixture stirred at ambient temperature for 24 h. Dilution with water followed by extraction with AcOE and washing the organic extracts with water, drying over anhydrous Na2SO4 and finally concentrating under reduced pressure gave crude alkylated product. Purification over silica gel using AcOEt/hexanes provided the desired 3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol (9.5 g, 78%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=CBr)c1ccccc1

Procedure:
100 g of N-bromosuccinimide are added to the mixture of 250 ml of α-methylstyrene and 40 ml of carbon tetrachloride. The resulting mixture is heated to reflux for 5 min. and cooled in an ice-water bath. Filtration and concentration give the desired compound, 1-bromo-2-phenylpropene, and an isomer thereof (65:35).
Reaction SMILES: [CH2:1]([N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])C#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.[OH-].[Na+].C(Cl)(Cl)Cl>OS(O)(=O)=O>[CH2:22]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCN(C#N)CCCCCCCCCCCCCCCCCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reaction time: 1 h
Yield: 42.2 %

Procedure:
The crude dioctadecylcyanamide (38 g) was suspended in 2.75 M H2SO4 (150 mL) and the mixture was refluxed for 2.5 h. After cooling to room temperature H2O (100 mL), 30% NaOH (100 mL) and CHCl3 (300 mL) were added. The organic phase was separated, dried and evaporated. The solid residue was suspended in Et2O and stirred for 1 h. The solid was filtered and washed with to give the desired compound (15.3 g; 29.3 mmol). Yield 48%. K.F.: 0.20%. The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][O:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:8]=1[C:9]([NH:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2)=[O:10]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CC[C@H](O)CO)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
Methanesulfonylchloride (0.08 mL) was added to a solution of 2-chloro-5-[(3S)-3,4-dihydroxybutyl]-N-(tricyclo(3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 1b) (0.33 g) and triethylamine (0.33 ml) in dichloromethane (10 mL). After 1 hour the reaction mixture was concentrated, redissolved in ethyl acetate and the organic layer washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Purification by normal phase HPLC (gradient 0–5% ethanol (EtOH) in dichloromethane on silica Novapak™ column), gave the sub-titled compound (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:18])[C:6](=[O:19])[C:5]=2[CH:4]=1.C[O-].[Na+].Cl.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CO.ClC1C=CC=CC=1>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:18][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]2=[O:19])[CH3:25]
Reactant: COc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)cc1C2=O
Yield: 64.9 %

Procedure:
Similar to example 3D1, prepare a solution of 2,4-dimethoxy-5-hydroxy-fluoren-9-one (0.33 g, 1.3 mmol) in methanol (8 mL) and 24 mL chlorobenzene with sodium methoxide (0.11 g, 2.0 mmole), and react the free base of 2-chloro-ethyl-diethyl amine hydrochloride 2.1 g (12 mmole) in order to obtain 0.30 g of the title compound as a reddish-orange powder. m.p. 178° C.-180° C. Analysis calculated for C21H25NO4.HCl: C, 64.36; H, 6.69; N, 3.58. Found: C, 63.99; H, 6.75; N, 3.62.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6][CH:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[C:4]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]>>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[C:36]([OH:38])=[O:37])=[C:4]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl
Yield: 65.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in U.S. Pat. No. 7,074,784) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.54 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[F:31][C:32]([F:38])([F:37])[CH2:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([C:34](=[O:35])[CH2:33][C:32]([F:38])([F:37])[F:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Reactant: O=C(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)CC(F)(F)F)C1
Yield: 70.5 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (100 mg, 0.226 mmol), and 3,3,3-trifluoropropionyl chloride (137 mg, 0.905 mmol) in dry pyridine (754.3 μL). Add 4-N,N-dimethylpyridine (2.9 mg, 0.0226 mmol) and stir the solution overnight. Add NaHSO4 solution and extract with EtOAc (2×20 mL). Combine the organic portions and wash with water (10 mL). Dry the organic solution with Na2SO4, filter, and concentrate in vacuo. Purify the crude material on silica gel chromatography, using an isocratic gradient of 80% EtOAc in hexanes, to give 88 mg (70%) of the title compound as a yellow solid. ES/MS m/z (35Cl) 552.8 [M+1]−.
Reaction SMILES: [N:1]1[C:10]2[C:4]([CH2:5][CH2:6][N:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)=[CH:3][N:2]=1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]([C:21]([NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=2)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: C1=C2CCN=c3ccccc3=C2N=N1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 396, (0.1 mmol) of 4,5-dihydropyrazolo[4,3-d][1]benzazepine is reacted with (0.21 mmol) of 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride to give the product as a light tan solid. Recrystallized from ethyl acetate/hexane, m.p. 228° C.-234° C. as white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1.C(OC(N1CCO[C@@H](C2C=CC(N)=C([F:47])C=2)C1)=O)(C)(C)C>>[ClH:2].[C:24]([C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([CH3:23])[N:20]=1)[C:16]([NH:15][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:3][C:4]=1[F:47])=[O:26])#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Reactant: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid (described in example 112) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 1-h) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].[CH3:35][OH:36]>>[CH3:35][O:36][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: CO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cn1
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OC

Procedure:
To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).