Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[C:8]([NH:10][C:11]1[CH:42]=[CH:41][C:14]([C:15]([N:17]([CH3:40])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:43][CH3:44])=[O:9].[C:49]([OH:58])(=[O:57])[C@@H:50]([C@H:52]([C:54]([OH:56])=[O:55])[OH:53])[OH:51]>C(O)C.O>[C:54]([CH:52]([CH:50]([C:49]([OH:58])=[O:57])[OH:51])[OH:53])([OH:56])=[O:55].[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[C:8]([NH:10][C:11]1[CH:42]=[CH:41][C:14]([C:15]([N:17]([CH3:40])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:43][CH3:44])=[O:9]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCN
Solvent: O
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (10.7 g) in ethanol (155 ml) was added a solution of L-(+) tartaric acid (2.43 g) in ethanol (60 ml) at 80° C. The solution was stirred at ambient temperature for 1 hour. The solvent was removed at reduced pressure and resulting solid was dissolved in distilled water (1 l) and the solution was filtered through micro filter and the filtrate was lyophilized to give 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide tartrate (5.2 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.1 mL of triethylamine and 1.3 mL of benzoyl chloride were added to 19 mL of methylene chloride solution containing 1.9 g of methyl 2-amino-4-methoxybenzoate while ice-cooled sequentially and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and chloroform and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 2.6 g of methyl 2-(benzamido)-4-methoxybenzoate as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cc1
Product: COCCOCOc1ccc(C=O)cc1
Yield: 81.4 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: [N:1]([CH2:4][C@@:5]1([CH3:15])[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:35]>C(#N)C>[ClH:35].[NH2:1][CH2:4][C@@:5]1([CH3:15])[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2
Reactant: C[C@]1(CN=[N+]=[N-])OB(O)c2ccccc21
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@]1(CN)OB(O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
(S)-3-(azidomethyl)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (700 mg, 3.45 mmol) and triphenyl phosphine (1.8 g, 6.9 mmol) were dissolved in 35 mL of acetonitrile. After 5 min concentrated hydrochloric acid (6.9 mL) was added and the reaction mixture was stirred for 24 hrs at room temperature before being concentrated under vacuum. The residue was taken up in DCM and washed 3× with 20 mL of 2M HCl. The combined aqueous layers were evaporated to dryness under vacuum. The resulting solid was washed with EtOH and filtered to remove byproducts, concentrated and crystallized from acetonitrile to give 160 mg (20%) of (S)-3-(aminomethyl)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([C:13]#[N:14])[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH2:14])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(C#N)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc2c(c1)CC(CN)CO2

Procedure:
0.51 g (2.7 mmol) of the nitrile obtained in Step A is reduced with lithium aluminium hydride in ether to yield the title amine in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:18])[F:16])[CH2:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[C:5]([Cl:27])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Yield: 25.2 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-chloro-benzoic acid methyl ester (807 mg, 1.79 mmol) in CH2Cl2 (100 mL) was added a solution of DIBAL (1.97 mL, 1 M in CH2Cl2, 1.97 mmol) with a syringe pump at −75° C. The mixture was stirred for 25 min at this temperature, before methanol (1 mL) was added and warmed to room temperature. Saturared aqueous Na/K-tartrate solution was added and the mixture was extracted three times with CH2Cl2. The organic layers were combined, dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (190 mg, 25%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].Cl>CC(C)=O.[OH-].[Na+]>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:11]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(NC(=O)c1ccccc1F)C(=O)O
Yield: 33.1 %

Procedure:
To a homogeneous solution of L-alanine(5 g, 56.1 mmol) in acetone (90 ml) and 1N NaOH (90 ml) was added 2-fluorobenzoyl chloride (8.9 g, 56.1 mmol) dropwise. Basicity of the reaction was maintained by adding 1N NaOH periodically. After the addition of 2-fluorobenzoyl chloride was completed, the reaction mixture was acidified to pH 2 using 1N HCl. The oil that precipitated out was extracted into EtOAc, which was dried over MgSO4, filtered, and concentrated to yield 2-(2-fluorobenzoylamino)propionic acid (intermediate XXIa, 3.92 g). Upon standing, more crystals of intermediate XXIa (2.3 g) precipitated from the acidic aqueous solution and were collected.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:18][CH:17]([CH3:19])[CH:16]([C:20]#[N:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.O>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH:17]([CH3:19])[CH:16]([CH2:20][NH2:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CN(Cc2ccccc2)CC1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)CC1CN
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of LAH (0.019 g, 0.499 mmol) in THF (5 mL) was added 1-benzyl-4-methylpyrrolidine-3-carbonitrile (0.050 g, 0.250 mmol, Tyger) at about 0° C., then the resulting mixture was stirred at about 25° C. for about 4 h. EtOAc (2 mL) and water (3 mL) were added and the precipitate formed was filtered off. The filtrate was concentrated to give (1-benzyl-4-methylpyrrolidin-3-yl)methanamine (0.05 g, 39%): LCMS (Table 2, Method 1) Rt=0.22 min.; MS m/z: 205 (M+H)+.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH3:6][CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][C:9](=[O:14])[CH2:8]1.[C-:15]#[N:16].[K+]>O>[OH:14][C:9]1([C:15]#[N:16])[CH2:10][CH:11]([CH3:13])[CH2:12][CH:7]([CH3:6])[CH2:8]1
Reactant: [C-]#N
Reactant: CC1CC(=O)CC(C)C1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1CC(C)CC(O)(C#N)C1
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 106.8 grams of sodium bisulphite in 130 ml. of water is added dropwise with stirring over 30 minutes to a stirred mixture of 100 grams of 3,5-dimethylcyclohexanone, 67.0 grams of potassium cyanide and 170 ml. of water. The reaction mixture is kept below 40° C. by means of a cold water bath. The reaction mixture is stirred for an additional 2 hours, the organic layer separated and the aqueous layer extracted with 250 ml. of ether three times. The combined organic layer and ether solutions are dried over magnesium sulfate and concentrated at reduced pressure to yield 40.3 grams of 1-hydroxy-3,5-dimethyl-cyclohexanecarbonitrile.
Reaction SMILES: N1C=CC=NC=1.[CH2:7]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[NH:21][C:20]([O:31][CH3:32])=[N:19][C:18]=1[CH2:33][CH3:34])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:7]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[N:21]([C:36]([O:38][CH3:39])=[O:37])[C:20]([O:31][CH3:32])=[N:19][C:18]=1[CH2:33][CH3:34])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)Cl
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1cncnc1
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 67.5 %

Procedure:
(−)-5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-methoxycarbonyl]pyrimidine. To a well stirred solution of (−)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAc as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine as a colorless oil.
Reaction SMILES: CNCC1C=CC=C(O)C=1.[CH3:11][C:12]([CH3:30])([CH3:29])[C:13]#[C:14]/[CH:15]=[CH:16]/[CH2:17][N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH2:19]C.CC(C)(C)C#C/C=C/CN(CC1C=CC=C(O)C=1)CCC.C(N(CC1C=CC=C(O)C=1)C/C=C/C#CC(OC)(C)C)C.CN.CO.C(N)C.C(N)CC.BrCC=CC#CC(OC)(C)C>CO>[CH3:11][C:12]([CH3:30])([CH3:29])[C:13]#[C:14]/[CH:15]=[CH:16]/[CH2:17][N:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH3:19]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: CCCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: CCN
Agent: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(O)c1
Solvent: CCCN
Solvent: CO
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1

Procedure:
The 3-hydroxybenzylamine derivatives used in Examples 26 to 48, such as (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-propyl-3-hydroxybenzylamine or (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxybenzylamine, were obtained by performing the same reaction as in Referential Example 26 except that in place of the starting methylamine-methanol solution, a methanol solution of ethylamine or propylamine was used and as required, 1-bromo-6-methoxy-6-methyl-2-hepten-4-yne was used instead of 1-bromo-6,6-dimethyl-2-hepten-4-yne was used.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])=[CH:9][C:8](/[CH:16]=[CH:17]/[CH2:18][O:19][CH3:20])=[CH:7][C:4]=1[CH:5]=[O:6].C>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[C:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:8]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COC/C=C/c1cc(C=O)c(OC)c(/C=C/COC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C=O)c(OC)c(CCCOC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Methoxy-3,5-bis[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde (1 eq.) from the previous step and 10% w/w palladium over charcoal (0.1 eq.) were suspended in EtOAc (0.1 M). The vessel was then evacuated and purged with H2. Under a balloon-filled H2 atmosphere, the reaction suspension was stirred at RT for 4 h. The reaction suspension was then quenched with dichloromethane and filtered through a bed of celite. Concentration of the filtrate in vacuo to afford the crude product as a yellow oil. Further purification by way of flash chromatography (SiO2, Hex→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][O:9][CH3:10].[OH2:21].C(Cl)(Cl)(Cl)Cl.CC#N>C(#N)C>[C:15]([O:14][C:13]([N:12]([CH3:20])[C@@H:6]([C@H:7]([CH3:11])[CH2:8][O:9][CH3:10])[C:2]([OH:1])=[O:21])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: O
Reactant: COC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC[C@@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of NalO4 (0.83 g, 3.87 mmol, 6.0 equiv) in water/CCl4/acetonitrile (3/2/3, 17.9 mL) was added RuCl3 (45.0 mg, 0.22 mmol, 0.34 equiv) at room temperature. After stirring for 15 minutes, a solution of compound 2.1c (0.183 g, 0.65 mmol) in acetonitrile (2.0 mL) was added. After stirring for another 15 minutes, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1b (0.17 g).
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[S:3].Br[CH2:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:4]=[C:2]([NH:1][C:5]3[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=3)[S:3][CH:17]=2)[CH:21]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CCOC(=O)c1ccc(NC(N)=S)cc1
Solvent: O
Product: CCOC(=O)c1ccc(Nc2nc(-c3cccnc3)cs2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 166.2 %

Procedure:
Ethyl 4-thioureidobenzoate (209 mg, 0.935 mmol) was added to a warm solution (50° C.) of 2-bromo-1-(pyridin-3-yl)ethanone (250 mg, 0.88 mmol) in water (5 mL) and stirred at 50° C. for 5 h. The precipitated was filtered out to afford the title compound 428 as a yellow solid (476 mg, wet) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[O:31][CH3:32])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.[CH3:33][NH2:34].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CO.CC(C1C=C(C(C)C)C(C2C(OC)=CC(Cl)=C(OC)C=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.[Pd+2]>[CH3:32][O:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[C:4]1[C:5]2[C:10](=[CH:9][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:34][CH3:33])[N:3]=1
Reactant: CN
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(Cl)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Agent: [Pd+2]
Agent: COc1cc(Cl)c(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CO
Product: CNc1cc2cc(S(=O)(=O)Nc3nccs3)ccc2c(-c2ccc(C(F)(F)F)cc2OC)n1
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A vial was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 249) (34.13 mg, 0.068 mmol) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(ii) (Strem Chemical, Newburyport, Mass.) (5.45 mg, 6.83 μmol), then flushed with Ar (g). Methanamine (2M in THF) (341 μl, 0.683 mmol) was added to give a solution. Lithium bis(trimethylsilyl)amide (1M in THF) (341 μl, 0.341 mmol) was added, resulting in the formation of a maroon solution. After 15 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-3-(methylamino)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (28.58 mg, 0.058 mmol, 85% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.81 (br. s., 1H), 8.11 (d, J=1.6 Hz, 1H), 7.53-7.42 (m, 3H), 7.36-7.24 (m, 3H), 6.88-6.82 (m, 1H), 6.79-6.71 (m, 2H), 3.75 (s, 3H), 2.82 (d, J=5.0 Hz, 3H); m/z (ESI) 495.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[CH3:43][CH:44]([CH3:48])[CH2:45][CH:46]=[O:47]>C1COCC1.C(Cl)Cl.O>[OH:47][CH:46]([C:11]1[C:6]2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[CH2:45][CH:44]([CH3:48])[CH3:43]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(C(F)(F)F)c3)cnc21
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CC(O)c1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.21 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 0.4 mL, 0.82 mmol) dropwise. The reaction was stirred at −78° C. for 40 min then 3-methylbutanal (35.9 mg, 0.42 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 5:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 50.8% yield) as a solid. LCMS: [M+-THP-OH] 465 and TR=2.180 min.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)C=CC=CC=1>>[C:1]1([N:9]2[C:10]3[C:15](=[C:14]([CH2:18][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:13]=[CH:12][CH:11]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: C=O
Product: c1ccc(-c2nn(-c3ccccc3)c3cccc(CN4CCNCC4)c23)cc1
Yield: 155.8 %

Procedure:
By the procedure similar to that described in Example 19, 3-phenylindazole (2.91 g), paraformaldehyde (0.50 g) and N-phenylpiperazine (4.87 g) were treated to obtain 4.3 g of 1-N-phenylpiperazinomethyl-3-phenylindazole having a melting point between 109°-110° C after recrystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15]>[Cu]I.CN1C(=O)CCC1>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1)#[N:15]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(C#N)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 133.2 %

Procedure:
Combined ethyl 2-(4-bromophenyl)acetate (30 g, 0.123 mol) and NMP (200 mL). Then CuCN (33 g, 0.370 mol) was added in portions and then degassed and refilled with nitrogen three times. Then CuI (4.7 g, 0.0247 mol) was added in one portion. The reaction was degassed and refilled with nitrogen three times and then heated to 160° C. for 4 hours. Then the reaction was heated to 180° C. for another 3 hours. The solution was then cooled to room temperature and diluted with EtOAc (500 mL) and water (500 mL). After stirring for 10 mins, the reaction was filtered and the aqueous layer was extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give the title compound (31 g, 66.5%) as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.S(=O)(=O)=O.P([O-])(O)(O)=O.[K+]>CS(C)=O>[Si:1]([O:8][CH2:9][C@H:10]([CH3:13])[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)CO[Si](C)(C)C(C)(C)C
Agent: O=P([O-])(O)O
Agent: O=S(=O)=O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](C=O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
(R)-(+)-3-(t-Butyldimethylsilyloxy)-2-methyl-1-propanol (3.0 g; 14.7 mmol) was added to a mixture of dimethylsulfoxide (20 ml) and triethylamine (13.4 ml), and a solution of the pyridine complex of sulfur trioxide (6.9 g; 43.3 mmol) in dimethylsulfoxide (20 ml) was added thereto at a temperature below 20° C. under stirring. Stirring was continued for 10 minutes, and an aqueous solution (80 ml) of 2M potassium dihydrogenphosphate and ice (40 g) were added thereto to stop the reaction. Insoluble materials were removed by filtration, and the filtrate was extracted with hexane (100 ml) three times. The organic layer was washed successively with water and aqueous sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure gave (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropanal (2.46 g; yield, 81%) as a colorless oil. The NMR spectrum of this product was identical to that of the product as obtained in Reference Example 2-1.