Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23](Br)=[CH:24][CH:25]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([S:30]([O-:32])=[O:31])C.[Na+].[C@@H]1(N)CCCC[C@H]1N>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:30]([CH3:28])(=[O:32])=[O:31])=[CH:24][CH:25]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)nc3)C2=O)CC1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)nc3)C2=O)CC1
Temperature: 110 °C
Yield: 100.4 %

Procedure:
A solution of (S)-tert-butyl-4-(3-(6-bromopyridin-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 0.714 mmol) in degassed DMSO (5 mL) was added sodium ethanesulfinate (117 mg, 1.15 mmol), trans-cyclohexane-1,2-diamine (33 mg, 0.286 mmol) and Cu(I) triflate benzene complex (54 mg, 0.107 mmol). The reaction was heated to 110° C. for 12 hours at which point the reaction was cooled to ambient temperature and partitioned between water (5 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to yield (S)-tert-butyl-4-(3-(6-(methylsulfonyl)pyridine-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 94%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:18][C:13]1[NH:14][C:15]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:16][C:12]=1[CH3:11]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C=C2C(=O)Nc3ccccc32)[nH]c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 147.8 mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 136.7 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:7]1([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)CCl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CNc1ccccc1
Yield: 9.6 %

Procedure:
The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide.
Reaction SMILES: [C:1]([O: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][CH2:18][C:19](Cl)=[O:20])(=[O:3])[CH3:2].O1CCN([C:28]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)CC1.C(Cl)(Cl)Cl.Cl.[OH2:45]>>[C:1]([O: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][CH2:18][C:19]([CH:39]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=[O:45])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCC(=O)Cl
Reactant: C1=C(N2CCOCC2)CCCCCCCCCC1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCCCCCCCCCCCCC(=O)C1CCCCCCCCCCC1=O
Temperature: 46 °C
Reaction time: 2 h

Procedure:
15-Acetoxy-pentadecanoyl chloride (151 g; 0.47 mole) was added to a stirred mixture of 1-morpholino-cyclododecene (133 g; 0.53 mole) and chloroform (500 ml, free of alcohol) under nitrogen during 35 minutes. The temperature raised to 46° C. After stirring for 2 hours a mixture of 82 ml of water and 125 ml of hydrochloric acid (36%) was added and this mixture was refluxed for 4 hours at 62° C. After cooling the flask to room temperature the layers were separated and the organic ##STR6## layer was washed with 250 ml of 1N hydrochloric acid. The water layer was extracted with 100 ml of chloroform. The combined chloroform layers were concentrated giving 240 g of crude (15-acetoxy-pentadecanoyl)-cyclododecanone.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.ClC1C=CC=C[N+]=1C.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:20]([O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccccc1
Yield: 83 %

Procedure:
To a CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium p-toluenesulfonate (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), benzoic acid (244 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2, and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl benzoate was isolated in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:24]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2cnc(Cl)nc2)c1
Temperature: 110 °C
Reaction time: 10.5 h
Yield: 14.9 %

Procedure:
To a solution of 1.93 g (10.0 mmol) of 2-chloro-5-bromopyrimidine in 30 ml of toluene, 4.12 g (30.0 mmol) of potassium carbonate, 1.89 g (10.5 mmol) of 3-(methoxycarbonyl)phenylboronic acid and 1.0 g (0.87 mmol) of tetrakis(triphenyl phosphine)palladium (0) were added, and the reaction solution was stirred at 110° C. for 10.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-0/100 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 0.37 g of the title compound as a yellow solid (yield: 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[OH:34]OS([O-])=O.[K+].O>CN(C=O)C>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:17]([NH:16][C@H:14]([C:8]3[N:9]=[C:10]([C:12]([OH:34])=[O:13])[C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[CH3:15])=[O:33])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=S([O-])OO
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)O)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348) (12.0 g, 26.3 mmol, 1.0 eq) in DMF (150 mL), OXONE (30 g, 48.78 mmol, 1.85 eq) was added and the resulting mixture was stirred at RT over night. The mixture was poured into water (600 mL) and then filtered. The solid was dissolved in ethyl acetate (100 mL), and then PE (300 mL) was added dropwise to this solution. The precipitate was collected by filtration to afford (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.[N:25]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.CN1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.CN(C=[O:56])C>CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[CH:5][CH:6]=1.[CH2:50]([O:49][C:48](=[O:56])[CH2:47][C@@H:2]([CH2:3][CH2:4][C:5]1[C:28]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:25][CH:6]=1)[NH2:1])[CH3:51]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN1CCOCC1
Reactant: CN(C)C=O
Agent: CN(CC(=O)O)C(=O)CCCc1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)CCc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
Acid 6-2 (288 mg, 1.22 mmol), amine 4-4 (318 mg, 1.22 mmol), BOP (647 mg, 1.5 mmol), and NMM (462 μL, 4.2 mmol) were combined in 6 mL DMF. After stirring overnight the mixture was diluted with EtOAc, washed with water (4×), sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, EtOAc then 5% MeOH/EtOAc) provided 6-3 as an orange oil.
Reaction SMILES: [K].[O-]CCCC.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][O:25][CH2:26][CH:27]([OH:29])[CH3:28]>>[CH3:28][CH:27]([O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:26][O:25][CH3:24]
Reactant: COCC(C)O
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CCCC[O-]
Agent: [K]
Product: COCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C
Yield: 84.7 %

Procedure:
To a stirred solution of potassium t.butoxide (9.3 g, 82.8 mmol) in 1-methoxy-2-propanol (70 ml) was added 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated to 80-90° C. for 4 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, concentrated to give a brown oil (7.2 g, 84.7%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[C:27]([NH2:32])[C:26]3[N:33]=[C:34]([CH2:39][O:40][CH2:41][CH3:42])[N:35]([CH2:36][CH2:37][CH3:38])[C:25]=3[C:24]=2[CH:23]=1.O>ClCCl>[NH2:32][C:27]1[C:26]2[N:33]=[C:34]([CH2:39][O:40][CH2:41][CH3:42])[N:35]([CH2:36][CH2:37][CH3:38])[C:25]=2[C:24]2[CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCCCCN)cc3c21
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCCCCNC(=O)C(C)C)cc3c21
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Isobutyryl chloride (0.236 mL, 2.25 mmol) was added dropwise, followed by triethylamine (0.2 mL, 1.4 mmol), to a stirred slurry of 8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (0.900 g, 2.25 mmol) in dichloromethane (25 mL) at room temperature. After 30 minutes, water (15 mL) was added and the mixture was allowed to stir for 30 minutes. The layers were separated and the aqueous layer was extracted with dichlormethane. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient elution with 1-6% CMA in chloroform) followed by recrystallization from acetonitrile afforded 0.285 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-2-methylpropanamide as a white crystalline solid, mp 136-138° C.
Reaction SMILES: [CH3:1]O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([S:13][C:14](C)([CH2:17][CH3:18])[CH:15]=[O:16])[N:6]=1.B.[Na]>O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([S:13][CH:14]([CH:17]([CH3:18])[CH3:1])[CH2:15][OH:16])[N:8]=1
Reactant: CCC(C)(C=O)Sc1nc(OC)cc(OC)n1
Reactant: CO
Agent: B
Agent: [Na]
Solvent: O
Product: COc1cc(OC)nc(SC(CO)C(C)C)n1

Procedure:
To a methanol solution of 2-(4,6-dimethoxy-2-pyrimidinylthio)-methyl butyraldehyde (1.5 g) was added sodium boron hydride (0.2 g), followed by a five-minute stirring at room temperature. Water was then added to the reaction liquid, followed by extraction with ethyl acetate, water-washing of the resulting organic layer and drying thereof in that order. After the removal of the drying agent from the reaction product under filtration, followed by separation of ethyl acetate under reduced pressure distillation, there was obtained an oily substance that was then purified by silica gel column chromatography to obtain the desired 2-(4,6-dimethoxy-2-pyrimidinylthio)-3-methylbutanol (1.3 g) n20D 1.5445.
Reaction SMILES: [C:1]([C:5]12[CH2:12][O:11][C:8]([CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:9][CH2:10]1)[O:7][CH2:6]2)([CH3:4])([CH3:3])[CH3:2].CC(C)(C)CCC12OCC(CCC)(CO1)C(C#N)O2.CC(C)(C)CCC(O)=O>>[C:1]([C:5]12[CH2:6][O:7][C:8]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:9][CH2:10]1)[O:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CCC12OCC(C(C)(C)C)(CO1)CO2
Agent: CC(C)(C)CCC(=O)O
Agent: CCCC12COC(CCC(C)(C)C)(OC1)OC2C#N
Product: CC(C)(C)C#CC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
Using analogous methodology 4-t-butyl-1-(3,3-dimethylbutyl)-2,6,7-trioxabicyclo[2.2.2]octane and 1-(3,3-dimethylbutyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile were prepared from 4,4-dimethylpentanoic acid (G. M. Whitesides et al J. Amer. Chem. Soc. 1967, 89, 1135).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(Cl)(Cl)Cl.C(OCC)(=[O:30])C>>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C:3]=1[CH2:12][C:13](=[O:30])[NH:14][CH:18]2[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccccc1Cl
Reactant: N#CCc1ccc2ccccc2c1Br
Solvent: ClC(Cl)Cl
Product: O=C1Cc2c(cc3ccccc3c2Br)C(c2ccccc2Cl)N1

Procedure:
This compound was prepared from 1-bromo-2-naphthylacetonitrile and 2-chlorobenzaldehyde. m.p. 256°-257° C. (chloroform-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:39])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:7]=1.CC[N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.N>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:39])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH2:42])=[O:28])[CH:20]=[CH:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(N)=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reaction time: 16 h

Procedure:
A mixture of {3-[5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-phenyl}-acetic acid (Example 60) (0.177 mmol), EDC.HCl (0.222 mmol), HOBt (0.131 mmol) and Et3N (0.621 mmol) in CH2Cl2 (1.3 mL) at rt was treated with an ammonia solution (0.4N/THF) (0.52 mmol). After stirring for 16 h, the reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic layers were successively washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 7.08 min (HPLC 2); ESI-MS: tR=1.16 min, [M+H]+ 562/564 (LC-MS 1); TLC: Rf=0.14 (EtOAc).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][N:14]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a slurry of 6-bromo-4-((3S,4S)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide salt from Step 1 of Example 158 (500 mg, 1.073 mmol) and DIPEA (0.562 mL, 3.22 mmol) in DCM (5 mL) at 0° C. was added a solution of methanesulfonyl chloride (160 mg, 1.395 mmol) in 1 mL of DCM dropwise and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by addition of MeOH (˜1 mL) and was then concentrated to afford a solid which was suspended in water, stirred for 30 min. and collected by vacuum filtration and dried under vacuum to afford 380 mg (85%) of the title compound. HPLC (method B) retention time 2.75 min. LCMS (m+1)=416/418 (1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3[CH2:35]COC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(CCC(NN)=O)#[N:37].O1CCC(CC(NN)=O)C1>>[C:35]([CH2:31][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)=[O:5])=[N:26][N:27]=1)#[N:37]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: N#CCCC(=O)NN
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CCC#N)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 3-cyanopropanehydrazide (compound 140.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 439 (M+H)+. 1H-NMR (300 Hz, CD3OD): δ 7.68 (d, 2H), 7.58-4.47 (m, 3H), 7.30 (s, 1H), 4.89-4.80 (m, 1H), 3.65-3.62 (m, 1H), 3.32-3.30 (m, 1H), 3.15 (t, 2H), 3.03-2.95 (m, 4H), 2.50 (s, 3H), 2.42 and 2.32 (2 singlets, amide rotamers, ArCH3, 3H), 2.03-2.00 (m, 1H), 1.83-1.78 (m, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=C.NCC[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][SiH:9]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:12].[NH2:4][CH:1]([CH3:2])[CH2:8][Si:9]([O:10][CH2:11][CH3:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: C=CCN
Product: CCO[SiH](OCC)OCC
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 120 °C

Procedure:
A four-neck flask equipped with a reflux condenser, dropping funnel, stirring rod and thermometer was charged with 41 grams of triethoxy silane (0.25 mole) and a solution of chloroplatinic (IV) acid as a catalyst, in isopropyl alcohol in an amount to provide 2×10-5 mole of platinum. To the mixture heated in an oil bath maintained at a temperature of 120° C., 14 grams of allylamine (0.25 mole) was dropwise added over one hour from the dropping funnel. The mixture was maintained at 120° C. for another period of 9 hours. At the end of the period the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 44% on a triethoxy silane basis, while the yield of beta-aminopropyl triethoxy silane was 10% on a triethoxy silane basis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH:14]([OH:16])[CH3:15].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:16]([CH:14]([CH3:15])[CH2:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(O)CBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1ccc2[nH]nc(I)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(Cn1nc(I)c2cc(F)ccc21)O[Si](C)(C)C(C)(C)C
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from 5-fluoro-3-iodo-indazole and 1-bromo-2-propanol according to the general procedure for Preparation 11A, followed by alcohol protection using TBDMS chloride (1.1 eq) and DMAP (1.1 eq) in DCM. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.06 (6H, s), 0.89 (9H, s), 2.07-2.13 (2H, m), 3.55 (2H, t, J=6.0 Hz), 4.49 (2H, t, J=6.0 Hz), 7.10 (1H, dd, J=2.4, 8.4 Hz), 7.18 (1H, td, J=2.4, 8.8 Hz), 7.40 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@@H:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: CCc1cc2c(Cl)ncnc2s1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ncnc2s1
Yield: 98 %

Procedure:
1-BOC-3-(S)-methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=98%, ES-MS: (M+H)+ 363.
Reaction SMILES: [Na].N.[C:3](#[N:5])[CH3:4].[C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)#[N:7]>C(OCC)C>[NH2:7][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1ccc2ccccc2c1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: N#CC=C(N)c1ccc2ccccc2c1
Yield: 22.2 %

Procedure:
To a solution of 2.0 grams (0.087 mole) of sodium in 125 milliliters of liquid ammonia was added a solution of 3.67 grams (0.089 mole) of acetonitrile in 10 milliliters of diethyl ether over a period of about five minutes. The reaction mixture was then cooled in a dry ice-acetone bath and a solution of 10.0 grams (0.065 mole) of 2-cyanonaphthalene in a minimum of dry diethyl ether was rapidly added within about five minutes after completion of the acetonitrile addition. The reaction mixture was stirred for about one and one-half hours and the ammonia was then allowed to evaporate. Water was cautiously added to the reaction mixture under nitrogen and the resulting mixture was extracted with diethyl ether. The ether was separated and the residue recrystallized from a mixture of chloroform and hexane. There was obtained 2.8 grams (22% of theoretical) of β-amino-β-(2-naphthyl)acrylonitrile, melting point 85°-90°C. Analysis: -- Calculated for C13H10N2 (percent): C, 80.39; H, 5.19; N, 14.42. Found (percent): C, 80.08; H, 4.99; N, 14.06.