Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH:14]=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][N:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1CCNCC1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C=C1CCN(CCN(C)C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH—AcOH (10:1, v/v, 22 ml) was added NaBH3CN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addition of sat. NaHCO3 (200 ml) and extracted with CHCl3 (3×150 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica-gel with CHCl3—EtOH (40:1, v/v) to give ethyl 1-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 1H-NMR (CDCl3) δ1.25 (t, J=7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 (m, 4 H), 2.95 (m, 7 H), 3.44 (m, 2 H), 4.13 (q, J=7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49-5.53 (m, 1 H), 7.35 (m, 5 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][C:17]#[N:18])[CH3:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:19])[C:16]([C:17]#[N:18])=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:13]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a stirred solution of 1,4-dioxa-spiro[4.5]decan-8-one (261) (5.0 g, 32.01 mmol) and cyano-acetic acid ethyl ester (3.99 g, 35.31 mmol) in toluene (50 mL) were added acetic acid (0.3 mL, 5.09 mmol) and ammonium acetate (123 mg, 1.60 mmol). A Dean Stark trap and reflux condenser were attached to the reaction flask and the mixture was heated to reflux and stirred for 16 h. Thereafter, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3 (100 ml). The aqueous layer was extracted with ethyl acetate (2×200 ml) and the combined organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude yellow oil was re-crystallized with 20% ethyl acetate in hexane to afford pure cyano-(1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester (262) (3.2 g, 39.78%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[C-:10]#[N:11].[Na+].CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][C:10]#[N:11])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(CC#N)OCC
Reaction time: 5 h

Procedure:
A mixture of 8 g of bromo-acetaldehyde diethyl-acetal, 3 g of sodium-cyanide and 20 ml of dimethyl-sulfoxide is admixed at a temperature of 80° C. for 5 hours. The reaction mixture is poured on 80 ml of water, then twice extracted with 50 ml of chloroform. The chloroform extract is washed twice with 30 ml of water, dried on magnesium sulfate, then distilled in vacuo.
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[CH:14]1([C:7]([OH:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml of tetrahydrofuran, 70 ml of 2.0 M cyclopentylmagnesium chloride solution in diethyl ether was added dropwise under cooling with ice, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off-under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=30/1-20/1) to provide 11 g of ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate, which was dissolved in 40 ml of methanol. To the solution 20 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by stirring for 2 hours at the same temperature and further for 1 hour at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was washed with 1:1 mixture of diethyl ether and hexane. Thus, 8.7 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][C:10]=2[CH3:16])[CH2:5][CH2:4]1)[CH3:2].[BrH:17].N([O-])=O.[Na+]>O.[Cu]Br>[Br:17][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[C:10]([CH3:16])[CH:11]=1
Reactant: Br
Reactant: CCN1CCN(c2ccc(N)cc2C)CC1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN1CCN(c2ccc(Br)cc2C)CC1
Temperature: 60 °C

Procedure:
4-(4-Ethyl-piperazin-1-yl)-3-methyl-phenylamine (1.3 g, 6 mmol) in hydrobromic acid (61% in H2O, 9.2 ml, 70 mmol) is diazotized at 0° C. with sodium nitrite (443 mg, 6.42 mmol) in 2.3 ml H2O and the mixture is poured into a solution of copper(I) bromide (1.84 g, 12.5 mmol) in hydrobromic acid (61% in H2O, 7.7 ml, 58.8 mmol) at 0° C. The cooling bath is then removed and the mixture is heated at 60° C. for 5 h. After cooling, the mixture is basified with a 2M NaOH solution and diluted with CH2Cl2. After separation, the aqueous phase is extracted with CH2Cl2 several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>4:6) to afford the title compound as a pale brown solid, Rt=0.878 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 283 (M+1, 79Br)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13]([C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:17]=1[NH2:18])([CH3:15])[CH3:14].C(N(CC)CC)C.[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>ClCCl>[CH3:24][CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:16]([CH:13]([CH3:15])[CH3:14])[C:17]=1[NH:18][C:10](=[O:12])[C@@H:2]([NH:1][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Reaction time: 16 h

Procedure:
To a solution of 0.61 g (1.88 mmol) (2,6-diisopropylaniline)-L-phenylalanine and 0.3 mL triethylamine in 20 mL dichloromethane at 0° C. was added 0.38 g (2.0 mmol) tosyl chloride. After 30 minutes the cool bath was removed and the reaction was stirred for 16 hours. The reaction mixture was taken up in dichloromethane and washed successively with dilute aqueous citric acid and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Obtained was a white powder that was recrystallized from diethyl ether. Yield: 0.75 g, mp 183°-184° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(OP(CCCCC1C=CSC=1Br)(=O)OCC)C>>[CH3:9][O:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([Br:8])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCCc1cccs1
Agent: CCOP(=O)(CCCCc1ccsc1Br)OCC
Product: COC(=O)CCCc1ccc(Br)s1
Yield: 90 %

Procedure:
The NBS bromination of 1b according to the procedure outlined for the preparation of 2a gave >90% yield of 2b as a colorless oil. b.p.: 138° C. at 0.15 mmHg. 1H NMR (250 MHz, 25° C., CDCl3): δ6.82 (d, 1H, Ar—H), 6.52 (d, 1H, Ar—H), 3.64 (s, 3H, OCH3), 2.79 (t, 2H, CH2CO2Me), 2.33 (t, 2H, Ar—CH2), 1.93 (tt, 2H, CH2CH2CH2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.N[C:12]1[C:13](C)=[CH:14]C=[CH:16][CH:17]=1.Cl.C[N:21](C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]1([CH3:14])[C:3]([C:8]([NH2:21])=[O:10])=[CH:2][CH:16]=[CH:17][CH:12]=1.[NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccccc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Nc1nccnc1C(=O)O
Solvent: ClCCl
Product: Cc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (5.0 g, 35.94 mmol), methylene chloride (110 mL), 4-dimethylaminopyridine (10.98 g, 89.85 mmol), o-toluidine (4.22 mL, 39.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.27 g, 43.13 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was diluted with ethyl acetate. This organic phase was extracted with 1 N lithium chloride (LiCl), water, and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (2.75×4 inches) with elution proceeding as follows: hexane (300 mL), nil; 20% ethyl acetate/hexane (500 mL), unweighed recovered o-toluidine; 20% ethyl acetate/hexane (1000 mL) and 30% ethyl acetate/hexane (2000 mL), 4.79 g (58%) of 3-aminopyrazine-2-carboxylic acid o-toluamide as a yellow crystalline solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [BrH:1].C(O)(=O)C.C(OC([NH:16][CH:17]1[CH2:19][CH:18]1[C:20]1[C:21]([F:38])=[CH:22][C:23]2[C:33](=[O:34])[C:32]([C:35]([OH:37])=[O:36])=[CH:31][N:25]3[C@@H:26]([CH3:30])[CH2:27][O:28][C:29]=1[C:24]=23)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>O>[BrH:1].[NH2:16][CH:17]1[CH2:19][CH:18]1[C:20]1[C:21]([F:38])=[CH:22][C:23]2[C:33](=[O:34])[C:32]([C:35]([OH:37])=[O:36])=[CH:31][N:25]3[C@@H:26]([CH3:30])[CH2:27][O:28][C:29]=1[C:24]=23
Reactant: C[C@H]1COc2c(C3CC3NC(=O)OCc3ccccc3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H]1COc2c(C3CC3N)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To 0.5 ml of a 30% hydrogen bromide-acetic acid solution was added with ice-cooling, 50 mg of (S)-10-(2-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 5 ml of chloroform and 5 ml of water in this order. The aqueous layer was separated. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained and the resulting crystals were collected by filtration to obtain 30 mg (yield: 68.2%) of (S)-10-(2-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hydrobromide.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](=[O:38])[N:35]([CH3:37])[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34](=[O:38])[N:35]([CH3:37])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cn1nc2ccc(Cl)nn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
0.52 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3 ml of N,N-dimethylformamide; 0.0704 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. 0.325 g of 6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was added, followed by stirring at room temperature for 2 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.502 g of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1ccc2cc(C(=O)O)ccc21
Reaction time: 12 h

Procedure:
Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccccc1NC(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1NC(=S)c1ccc(C)cc1
Temperature: 50 °C
Yield: 108.8 %

Procedure:
The 4-methyl-2'-methoxybenzanilide (50.0 g) obtained in (1) was dissolved in 200 ml of toluene, and 46.1 g of Lawesson's reagent was added. The mixture was refluxed for 1 hour. After the reaction, the reaction mixture was cooled to about 50° C., and 200 ml of water was added. The mixture was further refluxed for 2 hours. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was evapoated under reduced pressure. The residue was recrystallized from methanol and then cyclohexane to give 31.9 g of 4-methyl-2'-methoxybenzothioanilide. mp 91.0°-93.0° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([OH:11])[CH:10]=1.Cl[CH2:28][C:29](Cl)=[O:30].S(=O)(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH3:26][Si:2]([CH3:1])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:29](=[O:30])[CH2:28][O:11][C:9]=2[CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CNc2ccc(CO[Si](C)(C)C(C)(C)C)cc2O)cc1
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)COc3cc(CO[Si](C)(C)C(C)(C)C)ccc32)cc1

Procedure:
To a stirred solution of 5-(dimethyl-t-butylsilyl)oxymethyl-2-(4-methoxybenzylamino) phenol in anhydrous dichloromethane, triethylamine and dimethylaminopyridine at 0° C. and under nitrogen atmosphere, chloroacetyl-chloride is added. The mixture is refluxed for 10 h, poured into aqueous sodium bisulfate, extracted with dichloromethane and the product isolated by flash chromatography.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 52 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (840.3 mg, 52%); ES+-HRMS m/e calcd for C29H39N5O4SiF2 [M+H+] 588.2812 found 588.2817. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H), 0.80 (s, 9H), 1.08 (br s, 2H), 1.22-1.79 (m, 7H), 1.83-2.03 (m, 1H), 2.17-2.34 (m, 1H), 3.85 (t, J=5.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 5.46 (dd, J=10.7, 4.4 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.32-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:23]([CH:26]([CH3:28])[CH3:27])([O-:25])=[O:24].C(O)C.CC[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:22])[CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[C:26]([CH3:28])([N+:23]([O-:25])=[O:24])[CH3:27])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)C=Cc2ccncc2)cc(OC)c1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(=O)CC(c2ccncc2)C(C)(C)[N+](=O)[O-])cc(OC)c1OC

Procedure:
A solution of 40 g. of 3',4',5'-trimethoxy-3-(4-pyridyl)-acrylophenone and 24 g. of 2-nitropropane in 270 ml. of ethanol is heated at reflux with stirring under a nitrogen atmosphere. Within 1 hour there is added dropwise a sodium ethylate solution (manufactured from 1.35 g. of sodium and 27 ml. of ethanol). The reaction mixture left standing for a half hour to react further is then evaporated under reduced pressure. The residue results is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The product which results is crystallized with chloroform ether to yield 3',4',5'-trimethoxy-4-methyl-4-nitro-3-(4-pyridyl)-valerophenone, melting point 214°-216° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:14]#[N:15])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#C[Cu]
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reaction time: 0.2 h
Yield: 23.9 %

Procedure:
A stirred suspension of 4-amino-2,6-dichloro-3-nitro-pyridine (17.5 g, 841 mmol) and copper (i) cyanide (15.1 g, 168.3 mmol) in 170 ml of 1-methyl-2-pyrrolidinone was lowered into an oil bath preheated to 180° C. and stirring continued for 12 minutes. The mixture was allowed to cool and diluted with ethyl acetate (700 ml) and water (700 ml) and the resultant suspension filtered. The organic layer was separated and further washed with water (500 ml) and 0.1N HCl (500 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was washed with diethylether and dichloromethane to afford 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[CH2:42]([Sn](CCCC)(CCCC)CCCC)[CH:43]=[CH2:44]>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.CN(C=O)C>[CH2:44]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)[CH:43]=[CH2:42]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Temperature: 90 °C

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (see Example 70, step 3; 0.185 g, 0.278 mmol), Pd(PPh3)4 (0.016 g, 0.014 mmol), and DMF (0.557 ml). Allyltributyltin (0.104 ml, 0.334 mmol) was added and the reaction was heated in a microwave reactor at 90° C. for 30 minutes. The reaction was concentrated and purified via column chromatography (40 g silica gel column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-allyl-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light pink solid. m/z (ESI) 626.3 (M+H)+.