Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCCC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (75 mg) was dissolved in DCM (5 mL). Pyrrolidine (19 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (160 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (59.2 mg) as a white solid.
Reaction SMILES: [C:1]([C@:3]12[CH2:20][CH2:19][C@@:17]3([CH3:18])[C@@H:13]([CH2:14][C@@H:15](CC([O-])=O)[CH2:16]3)[C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([OH:25])[CH:6]=[CH:5][C:4]2=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+]>CO>[C:1]([C@:3]12[CH2:20][CH2:19][C@@:17]3([CH3:18])[C@@H:13]([CH2:14][C@@H:15]([OH:27])[CH2:16]3)[C@@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([OH:25])[CH:6]=[CH:5][C:4]2=1)#[N:2]
Reactant: C[C@]12CC[C@]3(C#N)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](CC(=O)[O-])C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@]3(C#N)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Yield: 926.7 %

Procedure:
At room temperature, 0.43 g (1.27 mmol) of 9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate is stirred for 2 hours with 1.0 g (7.24 mmol) of potassium carbonate in 40 ml of methanol (1% water). Then, the methanol is distilled off in a vacuum, and the organic residue is dissolved in methylene chloride. The organic phase is washed with water and concentrated by evaporation. 3.5 g (93%) of 9α-cyano-estra-1,3,5(10)-triene-3,16α-diol is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1)[CH3:18]
Reactant: CCN(CC)CCCCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN(CC)CCCCOc1ccc(CN)cc1

Procedure:
According to a similar manner as that in Reference Example 78, 4-[4-(diethylamino)butoxy]benzonitrile obtained above was reduced by lithium aluminium hydride to give the title compound (quantitative). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: CS(N)(=O)=O.C1(S(N)(=O)=O)CC1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][C:57]([F:61])([F:60])[CH2:56][CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[CH2:42][CH2:41]1.[N:62]1([S:66]([NH2:69])(=[O:68])=[O:67])[CH2:65][CH2:64][CH2:63]1>>[N:62]1([S:66]([NH:69][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH:40]3[CH2:41][CH2:42]3)[C:44]([O:53][CH:54]3[CH2:59][CH2:58][C:57]([F:60])([F:61])[CH2:56][CH2:55]3)=[CH:45][C:46]=2[F:52])(=[O:68])=[O:67])[CH2:65][CH2:64][CH2:63]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.092 g, 46%): 1H NMR (300 MHz, DMSO-d6) δ 11.58 (br s, 1H), 7.14-7.06 (m, 2H), 4.80 (br s, 1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.87 (m, 11H), 0.89-0.82 (m, 2H), 0.67-0.61 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −92.0 (d, J=232 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −112.7 (s, 1F); MS (ES−) m/z 431.1 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[Br:24][CH2:25][C:26](Br)=O.C([O-])(=O)C.[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:26]([CH2:25][Br:24])=[N:15][N:14]=[C:12]3[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(Br)CBr
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2

Procedure:
In the manner given in Example 1, 7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with bromoacetyl bromide and after 1.5 hours with sodium acetate, then refluxed to give 8-nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.C(O)C.[O:5]=[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([NH:16]C(=O)C)=[CH:11][CH:12]=2)[NH:7]1>>[NH2:16][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[CH:15][C:6](=[O:5])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc2ccc(=O)[nH]c2c1
Agent: Cl
Solvent: CCO
Product: Nc1ccc2ccc(=O)[nH]c2c1

Procedure:
A 1.2M hydrochloric acid-ethanol solution of N-(2-oxo-1,2-dihydroquinolin-7-yl)acetamide was heated under reflux to obtain 7-aminoquinolin-2(1H)-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=C[CH:20]=[C:19](Br)[CH:18]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cccc(Br)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a mixture containing piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (80 mg, 0.28 mmol) and sodium t-butoxide (400 mg, 4 mmol) in toluene (20 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (250 mg, 37% yield for two steps) as TFA salt.
Reaction SMILES: O=[CH:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5].O.[NH2:16][NH2:17].C(O)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:14][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:3]1[CH:2]=[N:17][NH:16][C:4]=1[NH2:5]
Reactant: Cc1cc(C)c(C(C#N)C=O)c(C)c1
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c(-c2cn[nH]c2N)c(C)c1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of 3-oxo-2-(2,4,6-trimethyl-phenyl)-propionitrile (2.300 g, 12.3 mmol), hydrazine hydrate (0.93 g) and glacial acetic acid (1.55 ml) in 20 ml benzene was heated at reflux for 4.5 hours. Reaction mixture was cooled to room temperature and 50 ml of 18.5% HCl in water was added. The benzene layer was separated and reextracted with 18.5% HCl. The aqueous layer were combined and neutralized with ammonium hydroxide and stirred at rt. overnight. Precipitate formed and was filtered to yield the title compound (0.256 g) as a yellow solid. The benzene layer was concentrated and purified through silica gel column using 5% methanol in chloroform as eluent to give an additional 1.450 g of the title compound; 1H NMR (CDCl3) ä 7.24(s, 1H), 6.95(s, 2H), 4.75(brs, 2H), 2.32(s, 3H), 2.13(s, 6H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:11](=[O:24])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].CO>ClCCl>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:24][CH2:31][CH3:32])[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CCc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1CC)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
275 mg (0.82 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-ethylbenzonitrile are suspended under an argon atmosphere in dichloromethane (10 ml), 313 mg (1.65 mmol) of triethyloxonium tetrafluoroborate are added, and the mixture is stirred at RT for 12 h. The reaction mixture is then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 152 mg (50% of theory) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[CH:2]=[C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[N:6]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(Cl)nc(Cl)n2)c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
Trichloropyrimidine (11.83 g, 64.49 mmol) was added to a solution of 3-methoxyphenylboronic acid (9.8 g, 64.49 mmol) in a solvent mixture of ethanol (30 mL), toluene (30 mL) and 2M aqueous sodium bicarbonate (96.7 mL) at rt. The resulting mixture was degassed under vacuum for several min before the flask was purged with nitrogen. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (2.4 g, 3.22 mmol) was added and the resulting mixture was heated for 3 h at 50° C. The cooled reaction mixture was filtered through a silica gel pad and the pad was washed with acetone. The filtrated was evaporated under reduced pressure. The crude material was purified by column chromatography eluting with a gradient of 0 to 45% ethyl acetate/hexanes to give 2,4-dichloro-6-(3-methoxy-phenyl)-pyrimidine as a white solid (14.4 g, 65.4%). MS ES 255 (M+H)+, calcd 255, RT=3.35 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)=[CH:15][C:14]([NH2:30])=[CH:13][N:12]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([NH:30][C:14]3[CH:13]=[N:12][C:11]([CH3:10])=[C:16]([NH:17][C:18]4[N:23]=[C:22]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=[CH:20][N:19]=4)[CH:15]=3)=[O:45])=[CH:47][CH:48]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cnc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (47 μL, 0.27 mmol) was added into a solution of 2-Methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (15 mg, 0.054 mmol), 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid (16.1 mg, 0.61 mmol), BOP (33.4 mg, 0.76 mmol) in DMF (1.5 mL). The reaction mixture is stirred at rt under argon atmosphere overnight. The reaction mixture was then purified by Waters semi-preparative HPLC to the final product. MS (ESI+) m/z 509.1 [M+H]+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:9])=[O:8])[CH:2]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1.CC1CCCCC1>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:12](=[O:13])[S:14][N:9]=2)[CH:2]=1
Reactant: Cc1cccc(C(N)=O)c1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Solvent: CC1CCCCC1
Product: Cc1cccc(-c2nsc(=O)o2)c1
Reaction time: 5.5 h
Yield: 45.8 %

Procedure:
m-Toluamide (116 g, 0.86 mol) and chlorocarbonylsulfenyl chloride (144 g, 1.1 mol, 28% excess) were heated to 100° C. in 400 ml of toluene, with stirring, for 5.5 hours. Cooling resulted in an orange solid. The solid, isolated by filtration, was dissolved in hot methylcyclohexane and decolorized. The light yellow product was recrystallized once from methyl-cyclohexane to give 76.05 g (45.8%) of white solid, m.p. 82. 5°-84°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]([C:26]3[N:27]=[CH:28][C:29]4[C:34]([C:35]=3[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:37]N1C(=O)CCC1=O>O1CCCC1>[Cl:37][C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH2:10][N:11]([C:26]3[N:27]=[CH:28][C:29]4[C:34]([C:35]=3[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)(=[O:14])=[O:13])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cc[nH]c3c2)c2ncc3ccccc3c2C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(Cl)c[nH]c3c2)c2ncc3ccccc3c2C)cc1
Reaction time: 17 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (177 mg, 0.36 mmol) prepared in Example 116 in tetrahydrofuran (1.8 mL) was added N-chlorosuccinimide (57 mg, 0.43 mmol) at room temperature, and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give ethyl 4-{[[(3-chloro-1H-indol-6-yl)methyl] (4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (124 mg, 65%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]C1(C(OC(C)(C)C)=O)CC1.[CH:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.BrCCCCBr.[Li+].CC([N-]C(C)C)C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Reactant: CCCCOC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: BrCCCCBr
Product: CCCCOC(=O)C1(CCCCBr)CCCC1

Procedure:
Compound 103c was prepared, likewise the procedure described for 103b, starting from butyl cyclopentanecarboxylate (Payne, G. B. et al. J. Org. Chem., 1957, 22, 1680-1682) (80.0 g, 0.42 mol), 1,4-dibromobutane (183.3 g, 0.84 mol) and LDA (2 M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) to give, after purification by fractional distillation under reduced pressure, 103c (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR: δ 4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR: δ 177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038, found: 304.1042.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:15]1[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(=O)=O>C1(C)C=CC=CC=1>[CH:19]([N:17]1[CH2:18][CH:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Phenol (2.2 g, 23.4 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 937 mg, 23.4 mmol) in toluene (40 ml) and the mixture was heated at 60° C. for 2 hours. The temperature was then increased to 80° C. and a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (4.78 g, 14.6 mmol) in toluene (80 ml) was added dropwise. After stirred at 80° C. for 2 hours, the resulting mixture was cooled to room temperature, then washed with water (100 ml) and brine (100 ml), dried over Na2SO4, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1. Collected fractions after solvent evaporation were further purified by preparative HPLC to afford the title compound (D20) (1.84 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.[H-].[Na+].[CH2:28]([OH:30])[CH3:29]>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([O:30][CH2:28][CH3:29])[N:7]2[N:8]=1
Reactant: CCO
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 6 h

Procedure:
To a solution of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 20 mg, 0.051 mmol) in ethanol (1 ml) was added NaH (60% dispersion in oil, 2 mg, 0.05 mmol), portionwise. After stirring for 6 hours, the reaction was concentrated, in vacuo. The residue was redisolved in methylene chloride, filtered through a 0.45 μm disk, and then concentrated to afford 12A-1 (18 mg, 88%) as a solid: +APcI MS (M+1) 399.1; 1H NMR (400 MHz, CD2Cl2) δ 7.50-7.37 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 4.80 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[H-].[Na+].Br[CH2:35][CH3:36]>CN(C=O)C>[CH2:35]([O:1][CH2:2][CH2:3][CH:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)[CH3:36]
Reactant: CCBr
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)C(CCO)CC4)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCC1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a 25-mL round-bottom flask was added a solution of intermediate 18.3 (125 mg, 0.28 mmol, 1.00 equiv) in distilled DMF (10 mL) followed by sodium hydride (60% dispersion in mineral oil, 96 mg, 2.80 mmol) at 0° C. and the reaction mixture was stirred for 30 min. Then bromoethane (305 mg, 2.80 mmol) was added and the resulting solution was stirred overnight at room temperature. The reaction was then quenched with water and extracted with 100 mL of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with EtOAc/petroleum ether (1:5). Purification afforded tert-butyl N-(4-[[3-(2-ethoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (19.1, 19 mg, 14%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([N:1]([CH2:15][C:12]4[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=4)[CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:24][CH2:23]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Oc2ccc(N(Cc3ccccc3)Cc3ccccc3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-benzylpiperazin-1-yl)propane-1-one (1.0 g, 2.4 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.73 g, 5.28 mmol), sodium iodide (0.76 g, 5.04 mmol) and benzyl bromide (0.60 mL, 5.04 mmol), and the resulting solution was stirred at room temperature overnight. This reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform methanol=80:1), to thereby yield 0.67 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:17]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:23][CH:22]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Yield: 93.8 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (123 mg, 443 μmol), 4-(4-morpholino)aniline (118 mg. 0.664 mmol) and N-ethyldiisopropylamine (116 mL, 0.664 mmol) is heated at reflux in 2-propanol (3 mL) for 4.5 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and citric acid (10%). The organic phase is washed once with water and brine, dried over MgSO4, filtered and evaporated to furnish the title compound (156 mg, 94%) as a yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.11 (m, 4H), 3.78 (m, 4H), 6.97 (d, 2H), 7.82 (d, 2H), 7.87 (s, 1H), 8.71 (s, 1H), 9.93 (br s, 1H). LCMS, Rt 3.32 min (96.8%) m/z (APCI) 375 (M+H)+.