Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=4[CH:16]=3)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]([C:44]3[CH:53]=[CH:52][C:51]4[C:50]([CH3:55])([CH3:54])[CH2:49][CH2:48][C:47]([CH3:57])([CH3:56])[C:46]=4[CH:45]=3)=[O:43])[CH:38]=2)[C:33]=1[CH2:58][CH3:59])(=[O:31])=[O:30])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=4[CH:16]=3)[OH:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:42]([OH:43])[C:44]3[CH:53]=[CH:52][C:51]4[C:50]([CH3:55])([CH3:54])[CH2:49][CH2:48][C:47]([CH3:57])([CH3:56])[C:46]=4[CH:45]=3)[CH:38]=2)[C:33]=1[CH2:58][CH3:59])(=[O:31])=[O:30])[CH3:2]
Reactant: CCc1c(S(=O)(=O)c2ccc3cc(C(=O)c4ccc5c(c4)C(C)(C)CCC5(C)C)ccc3c2CC)ccc2cc(C(=O)c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(S(=O)(=O)c2ccc3cc(C(O)c4ccc5c(c4)C(C)(C)CCC5(C)C)ccc3c2CC)ccc2cc(C(O)c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 200 mg of ethyl 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbonyl]-2-naphthylsulfone, obtained in accordance with Example XIV, in 30 cm3 of methanol cooled to 0° C., there are added 100 mg of sodium borohydride. The reaction mixture is maintained under stirring for 30 minutes, then it is returned to ambient temperature. After verification by thin layer chromatography of the disappearance of the starting carbonyl product, the alcohol is evaporated under reduced pressure and the residue is taken up in 100 cm3 of water and acidified with a solution of 1N HCl. The resulting precipitate is filtered and dried under a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].C(N(CC)CC)C>ClCCl>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[S:18][C@@H:16]([C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17]
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CN(C)C(=S)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](SC(=S)N(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.3 %

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-3-mercapto1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.10 g) was allowed to react with N,N-dimethylthiocarbamoyl chloride (0.13 g) in dichloromethane (3.0 ml) in the presence of triethylamine (49 ml) by the same manner as in Example 2. The compound (32), i.e., [(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl] N,N-dimethyldithiocarbamate (0.08 g) was obtained as colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>>[CH:1](=[N:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccccc1
Product: CC(C)(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
530.85 g (5.00 mol) of benzaldehyde was placed into a 2000 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel. Subsequently, 367.50 g (5.02 mol) of t-butyl amine was dropped into the flask in a water bath, while maintaining the solution temperature at 25° C. After the completion of the dropping, the mixture was reacted while stirring at 25° C. for 15 hours. After the completion of the reaction, the reaction mixture was subjected to separation, and the organic layer obtained was refluxed under reduced pressure (25° C., 13.3 Pa) for 2 hours, to provide 788.91 g of N-benzylidene-t-butyl amine. (Isolation yield; 98%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CCOC(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: c1ccc(CN2CCC(NC3CCOCC3)CC2)cc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
19 g of 4-amino-1-benzylpiperidine are placed in 50 ml of 1,2-dichloroethane under dry nitrogen and 10 g of tetrahydropyran-4-one in 20 ml of 1,2-dichloroethane are added; after stirring for 10 minutes, 29.6 g of NaBH(OAc)3 are added and the mixture is then stirred for one day. 10% Na2CO3 solution and EtOAc are added to the reaction medium and the phases are then separated by settling. The organic phase is washed with 10% Na2CO3 solution and then with saturated NaCl solution, and then dried over MgSO4 and evaporated under vacuum. 23.4 g of the expected compound are obtained. m.p.=60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:12]=1
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Yield: 35.9 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 1-iodopentane (0.07 mL, 0.7 mmol) to give the title compound (0.069 g) as a white solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCCCC2)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide to give the desired product as a colorless solid (89%).
Reaction SMILES: C([O:9][C:10]1[C:11]([C:27]([O:29]C)=O)=[N:12][C:13]([O:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:27]([C:11]2[C:10]([OH:9])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:20][CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[N:12]=2)=[O:29])=[CH:34][CH:33]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(OCC(=O)N(C)C)c2cccnc2c1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)COc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 110 °C

Procedure:
A mixture of methyl ester from Step 1 (0.28 g, 0.68 mmol) and 4-fluorobenzylamine (0.16 mL, 1.43 mmol) in toluene (5 mL) was heated in an oil bath at 110° C. overnight. The resultant precipitate was filtered, washed with diethyl ether, and dried under vacuum. The solid was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[N:18]1([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:29][CH2:28]1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: C1CCN(CC2CCNCC2)C1
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 68.3 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (250 mg, 0.800 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (168 mg, 1.00 mmol) to afford the desired product (243 mg, 68%) as a yellow solid: ESI MS m/z 444 [C23H30BrN3O+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[C:19]([CH3:20])=[N:18]1
Reactant: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 52 %

Procedure:
3.5 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 8.1 g of N-methylpiperazine and 50 ml of toluene are stirred at 80° C. for 2 hours. 60 ml of dilute sodium bicarbonate solution are added to the mixture, the layers are separated and the aqueous phase is extracted by shaking it with toluene several times more before concentrating it to dryness in vacuo. The residue is stirred with 100 ml of isopropanol and is filtered; the filtrate is concentrated in vacuo. The residue (4.0 g) is purified by stirring it with diethyl ether and by recrystallizing it from toluene, which yields 2.2 g of 1,3-dimethyl-4-[(4-methylpiperazin-1-yl)acetyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 186° to 188° C.; succinate, mp 172° to 174° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>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>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]2[CH:25]=[C:24]([CH2:23][CH:20]3[CH2:19][CH2:18][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:22][CH2:21]3)[CH:29]=[CH:28][CH:27]=2)[CH:7]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B(O)O)c2)CC1
Reactant: N#Cc1ccnc(Cl)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cc(C#N)ccn3)c2)CC1
Temperature: 140 °C
Yield: 56.5 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (416 mg, 3 mmol) was added {3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}boronic acid (958 mg, 3.00 mmol) followed by K2CO3 (1,244 mg, 9.00 mmol) and Pd(Ph3P)4 (139 mg, 0.120 mmol) in 1,4-dioxane (15 mL) and water (5 mL). The mixture was heated in a microwave oven for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 mL). The combined organic layers were filtered, concentrated on Glas-Col, redissolved in hexane/DCM (3:1, 4 mL), loaded onto Redisep silica gel column (40 g) and purified with Combiflash chromatograph to afford 640 mg (57%) of the title compound. LC-MS m/z 378 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](#[N:25])/[CH:21]=[CH:22]/[C:23]#[N:24]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:16]3)=[C:22]([C:23]#[N:24])[C:21]=2[C:20]#[N:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC[C@H]1CC[C@H](C=CC=CC2CCCCC2)CC1
Reactant: N#C/C=C/C#N
Product: CCC[C@H]1CC[C@H](c2ccc(C3CCCCC3)c(C#N)c2C#N)CC1

Procedure:
Using 1-cyclohexyl-4-(trans-4'-n-propylcyclohexyl)-1,3-butadiene and fumaronitrile, 3-cyclohexyl-6-(trans-4'-n-propylcyclohexyl)phthalonitrile was obtained by the same method as in Example 1. It was a monotropic nematic liquid crystal having m.p. of 102.5° C. and cl.p. of 92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>O1CCCC1.O>[Cl:37][CH2:38][C:39]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)=[O:40]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(C)cc3N)[nH]c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(C)cc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To a suspension of methyl 2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (638 mg, 1.6 mmol), sodium acetate (289 mg, 3.5 mmol) and acetic acid (0.10 ml, 1.8 mmol) in tetrahydrofuran (7 ml) was added dropwise chloroacetyl chloride (0.14 ml, 1.8 mmol), and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained crude product (640 mg) was used for Step 9 without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>COCCOC.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:13]1([C:11]([C:4]2[CH:3]=[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=2)=[O:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1cc(Br)cc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cc(-c2ccccc2)cc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 100 °C

Procedure:
A suspension of (3-bromo-5-nitrophenyl)(morpholin-4-yl)methanone (200 mg, 0.635 mmol), phenylboronic acid (101 mg, 0.825 mmol), sodium carbonate (101 mg, 0.952 mmol), tri-o-tolylphosphine (19.32 mg, 0.063 mmol) and palladium(II) acetate in DME (1.02 mL) and water (0.25 mL) was heated to 100° C. for 3 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate (50 mL), filtered through CELITE, and washed with brine (30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes) provided morpholin-4-yl(5-nitrobiphenyl-3-yl)methanone as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J=1.6 Hz, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.65 (d, J=7.3 Hz, 2H), 7.61-7.43 (m, 3H), 3.69 (dd, J=65.5, 62.1 Hz, 8H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C1C=CC=CC=1)([O-])=O>[C:9]1([C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cccc2ccccc12

Procedure:
A mixture of naphthalene (40 g) and succinic anhydride (20 g) was added to a well stirred suspension of aluminum trichloride (55 g) in nitrobenzene (140 ml). The resulting mixture was stirred overnight at room temperature. The mixture was then poured slowly onto ice-water (600 g) and acidified with 6N-hydrochloric add. The crude acid was filtered, washed with water until washings were neutral and recrystallized from ethanol yielding the product (m.p. 170°-172° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]O)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S(Cl)([Cl:27])=O>N1C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][Cl:27])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 6-bromo-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.7 g, 22.5 mmol) and pyridine (5 drops) in tetrahydrofuran (30 mL) and toluene (30 mL) was added thionyl chloride (3.4 mL, 47.3 mmol). The obtained mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.2 g, 90%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:14]2[CH2:15][CH2:16][O:11][CH2:12][CH:13]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cc(Br)cc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C2=CCOCC2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 12 h

Procedure:
In a microwave vial 2,5-dibromo-1,3-dimethylbenzene (800 mg), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (640 mg) and K3PO4 (1.3 g) are suspended in toluene (12 mL) and water (1.2 mL) and purged for 10 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium-(II) (100 mg) is added, the vial is sealed and the mixture is stirred at 60° C. for 12 hours. After cooling to room temperature the mixture is diluted with diethylether and washed with saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 404 mg.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH2:39]>C1(C)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([NH:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 7.6 %

Procedure:
To a solution of N-(tert-butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.400 g, 0.883 mmol) in toluene (5 mL) was added pyridin-2-ylmethanamine (0.0950 g, 0.883 mmol) and the contents were heated at 100° C. for 12 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 16 as described in general methods) to yield N-(tert-butyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridine-3-sulfonamide (35.0 mg, 7.55%) as a white solid. LCMS (Condition 4): retention time 2.47 min, [M+1]=525.2. HPLC (Condition 28): retention time=6.97 min, purity 96.32%. 1H NMR (400 MHz, CD3OD) δ 1.30 (s, 9 H), 4.68 (s, 2 H), 7.24 (dd, J=4.8 Hz, J=7.2 Hz, 1 H), 7.27 (d, J=7.6 Hz, 1 H), 7.52 (br s, 5 H), 7.72 (dd, J=1.6 Hz, J=7.6 Hz, 1 H), 7.77 (dd, J=1.2 Hz, J=7.2 Hz, 1 H), 7.84 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 7.91-7.96 (m, 1 H), 8.31 (d, J=4.4 Hz, 1 H), 8.55 (t, J=2.0 Hz, 1 H), 9.07 (d, J=2.0 Hz, 1 H), 9.18 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)CCCC>[N:16]1([CH2:15][CH2:14][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCO
Product: C1CCN(CCN2CCNCC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of anhydrous piperazine, 10.0 grams, (0.116 moles) and sodium carbonate (12.3 grams, 0.116 moles) in 70 cc of 1-pentanol brought to the boiling point, is added slowly over a period of four hours, N-(2-chloroethyl)piperidine, (11.3 grams; 0.077 moles) diluted with 150 cc of 1-pentanol. After boiling for an additional period of four hours, the mixture is allowed to cool, it is then filtered and evaporated under reduced pressure. The oily residue is subjected to column chromatography using methanol and concentrated ammonium hydroxide in the ratio of 95:5. The desired product is obtained as an oil, but after standing for a few hours, it solidifies. Melting point is 60°-62° from diisopropyl ether. It forms a picrate: melting point 235°-237° C. (from ethanol); Rf=0.21, (MeOH-NH4OH 9.5:0.5); IR (nujol) max: 3240, 2780, 2760, 1445, 1325, 1300, 1140, 1125, 1105, 865, 770 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1I
Temperature: 80 °C
Yield: 99 %

Procedure:
2-(2-Iodophenyl)acetic acid (5.00 g, 19.1 mmol) was placed into a reaction flask and dissolved in MeOH (150 mL). Sulfuric acid (250 μL) was added and reaction mixture was stirred and heated at 80° C. under nitrogen for 16 hours. The resulting mixture was cooled to room temperature and the volatiles removed by evaporation under reduced pressure. The residue was taken up in ethyl acetate (100 mL), washed with 10% NaHCO3 (100 mL), dried (MgSO4) and evaporated under reduced pressure to give the title compound (I9) (5.20 g, 99%) as a clear liquid; 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=7.9, 1.0 Hz, 1H), 7.35-7.27 (m, 2H), 6.97 (ddd, J=7.9, 7.0, 2.1 Hz, 1H), 3.81 (s, 2H), 3.72 (s, 3H).