Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:36])=[CH:27][C:28](=[O:35])[N:29]2[CH2:32][CH:33]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:19])[CH2:14][CH2:15][N:16]([CH2:33][CH2:32][N:29]4[C:30]5[C:25](=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:31]=5)[C:26]([CH3:36])=[CH:27][C:28]4=[O:35])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC1(NCc2ccc3c(c2)OCCO3)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(C)(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To 2 mL of dichloromethane solution containing 77 mg of N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylpiperidine-4-amine, 68 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 17 μL of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 93 mg of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1] to give 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidin-1-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:36](=[O:38])[CH3:37])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was placed in 1 ml DCM and treated with DIPEA (0.04 ml; 0.23 mmol) and acetyl chloride (0.04 ml; 0.57 mmol). It was stirred at ambient temperature for 4 hours. The crude reaction mixture was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])(CC)C.[CH2:34]([N:41]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C@@H:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:43]=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][C@@H:12]1[C@@H:43]([OH:44])[C@H:42]([N:41]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Dissolve commercially available tert-butyl 4-benzyl-1-piperazinecarboxylate (2.9 g, 10.4 mmol) in diethyl ether (75 mL) under argon and cool to −78° C. Add tetramethylethylene diamine (1. 8 mL, 11.7 mmol) and sec-butyllithium (9 mL, 11.7 mmol) dropwise at −78° C. React for 1.5 h and add 2-(S)-dibenzylamino-3-phenylpropionaldehyde (2.6 g, 7.9 mmol) in diethyl ether (18 mL) dropwise over 10 min. Stir for 45 min. Add saturated aqueous ammonium chloride solution and ethyl acetate and let warm to room temperature, separate the layers, extract the aqueous layer with ethyl acetate, wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate) to give the title compound (the first spot to elute) as a white solid (1.45 g, 30%) and a second diastereomer (the second spot to elute) as a white solid (1.1 g, 23%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:13]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)c1n[nH]c2ccccc12

Procedure:
This compound is synthesized in a manner similar to the procedure described in Example 2 by coupling indazole-3-carboxylic acid and N-phenyl-1,4-phenylenediamine on the scale of 1 mmol, but using dicyclohexylcarbodiimide (DCC) as coupling reagent. The crude product obtained after extraction is taken up in CHCl3. The insoluble matter is filtered and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:17])([CH3:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:13][C:12]([F:14])([F:15])[C:11]([CH3:16])([CH3:17])[O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1ccc(N)cc1)C(F)(F)F
Yield: 97.4 %

Procedure:
1-Nitro-4-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzene (4.9 g) in methanol (30 ml) was hydrogenated over Pd/C (10%, 500 mg) at RT and atmospheric for 12 h. The catalyst was filtered off and the solvent removed in vacuo to give the desired 4-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenylamine (4.2 g) as a brown oil that was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:23]=1)[C:5]([N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16]O[CH2:14][CH2:13]1)=[O:11])=[O:6].ClC1C=C(C=C(OCCNC2C=CN=CC=2)C=1)C(N(C(C)C)CCC(O)=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:23]=1)[C:5]([N:7]([CH:18]([CH3:19])[CH3:20])[CH2:8][CH2:9][C:10](=[O:11])[N:12]1[CH2:17][CH2:16][CH2:14][CH2:13]1)=[O:6]
Reactant: CC(C)N(CCC(=O)N1CCOCC1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Agent: CC(C)N(CCC(=O)O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Product: CC(C)N(CCC(=O)N1CCCC1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1

Procedure:
3-Chloro-N-isopropyl-N-(3-morpholin-4-yl-3-oxo-propyl)-5-[2-(pyridin-4-ylamino)-ethoxy]-benzamide mixture with 3-({3-chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-isopropyl-amino)-propionic acid (1:2);
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](#[N:29])[CH3:28].CO>C(OCC)(=O)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:8][CH2:7][CH2:6][CH2:11][CH2:28][CH2:27]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: CC#N
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc2c(-c3ccc(OCCCN4CCCCCC4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, hexamethyleneimine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=366.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:21])[C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:5][CH:4]=1.[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:18][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:21])=[O:31])=[CH:33][CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(NC(=O)c2c(C)cccc2[N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(NC(=O)c2c(C)cccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 16.5 %

Procedure:
Using the procedure described in Example 93, Part B, N-(4-methoxyphenyl)-2-nitro-6-methylbenzamide (1.05 mmol) was reduced to the corresponding amine. Using the procedure described in Example 93, Part A, the amine was reacted with 4-tert-butylbenzoyl chloride (1.05 mmol) to yield 72 mg (17%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][CH:23]([S:25]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)(=[O:27])=[O:26])[CH3:24]>CS(C)=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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[NH:28][S:25]([CH:23]([CH3:24])[CH3:22])(=[O:27])=[O:26])=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: CC(C)S(=O)(=O)Nc1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
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: CS(C)=O
Product: CC(C)S(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 80 °C
Yield: 9 %

Procedure:
To a solution of 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (309 mg, 1.15 mmol) in DMSO (5 mL) was added K2CO3 (317 mg, 2.3 mmol). The mixture was sparged with N2 several times. Pd(PPh3)4 (66 mg, 0.058 mmol) and (2-(1-methylethylsulfonamido)-phenyl)boronic acid (280 mg, 1.15 mmol) were added and the resultant mixture sparged with N2. The mixture was heated at 80° Celsius for 14 hours before cooling to rt and diluting with water (70 mL). The precipitate was collected, rinsed with water, air dried, and then purified by HPLC to give the title compound (40 mg, 9%). MS (ESI): mass calcd. for C19H19FN4O2S, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.72 (s, 1H), 8.25 (d, J=1.2, 1H), 8.16 (m, 1H), 7.50 (d, J=7.8, 1H), 7.47-7.34 (m, 5H), 3.15-3.03 (m, 1H), 1.23 (d, J=6.8, 6H).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>>[CH2:37]([O:36][C:34]([N:31]([CH2:30][C:15]1[CH:16]=[C:17]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:44])=[O:3])[CH:7]=1)[CH2:32][CH3:33])=[O:35])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCN(Cc1cc(NC(=O)c2ccc(Cl)cc2)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1

Procedure:
[2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-(4-chloro-benzoylamino)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester (0.2 mmol) was hydrolyzed with lithium hydroxide to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][C:20]2[N:24]([CH3:25])[CH:23]=[N:22][C:21]=2[N+:26]([O-:28])=[O:27])[N:3]=1.O(C)[Na].ClC1N(C)C=NC=1[N+]([O-])=O>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([Se:19][C:20]2[N:24]([CH3:25])[CH:23]=[N:22][C:21]=2[N+:26]([O-:28])=[O:27])[N:3]=1
Reactant: Cn1cnc([N+](=O)[O-])c1[Se]c1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CO[Na]
Agent: Cn1cnc([N+](=O)[O-])c1Cl
Solvent: CO
Product: Cn1cnc([N+](=O)[O-])c1[Se]c1nc(N)nc2c1ncn2[C@@H]1C[C@H](O)[C@@H](CO)O1
Yield: 91 %

Procedure:
The procedure was the same as that for 7c except that 800 mg (0.0024 mol) of 2, 160 mg of NaOCH3, and 400 mg of 5-chloro-1-methyl-4-nitroimidazole were used. The product obtained by crystallization from MeOH--H2O was dried over Drierite in vacuo at the temperature of refluxing toluene for 2 hr. to yield 1.0 g (91%) of 3c: mp 148° softens to a glass.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.[Cl-].[NH4+]>[F:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([I:1])=[CH:3][N:4]2[S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc2c(I)c[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
To a cooled (0° C.) solution of 3-iodo-6-fluoroindole (0.50 g, 1.92 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion, 115 mg, 2.87 mmol). The resulting mixture was then stirred at 0° C. for 5 minutes before the addition of benzenesulfonyl chloride (0.37 mL, 2.9 mmol). After stirring at 0° C. for 30 minutes, the reaction was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was then diluted with saturated ammonium chloride. The aqueous mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (0-50% gradient EtOAc-heptane) to give 6-fluoro-3-iodo-1-(phenylsulfonyl)-1H-indole (0.852 g, quant.).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.ClC1C=CC(C[CH:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]2=[O:27])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[S:1]1[C:5]([CH2:6][CH:18]2[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]2=[O:27])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1

Procedure:
The title compound was prepared using benzo[b]thiophene-2-carbaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH3:19])[CH2:27][CH2:28]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: NC(=O)c1cc2ccc(OCC3CO3)cc2o1
Agent: Cl
Product: Cc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 10 were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-6-(2,3-epoxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methylphenyl)piperazine hydrochloride were employed. The obtained residue was crystallized from ethyl acetate and ether.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:4][CH2:3]1>[Ni].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cn2)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 1-methyl-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step 39.2) (0.529 g, 2.24 mmol) and Raney nickel (0.1 g) in MeOH (10 mL) was stirred for 1 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 0.448 g of the title compound as an off-white solid: ESI-MS: 207.2 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25]>>[C:14]([O:8][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([O:1][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[N+:24]([O-:26])=[O:25])[CH2:3]1)=[O:9])([CH3:20])([CH3:15])[CH3:13]
Reactant: O=C(O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
deprotonating (R)-3-Hydroxypyrrolidine-1-carboxylic acid tent-butyl ester and further reacting the resultant compound with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene to form (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester;
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCBr
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetic acid salt (for example, as prepared for Intermediate 8) (5 g, 14.27 mmol) and potassium carbonate (4.93 g, 35.7 mmol) were suspended in DMF (40 mL) and heated to 50° C., under nitrogen for 30 minutes. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (commercially available, for example, from Aldrich) (1.645 mL, 14.27 mmol) was added and stirring was continued at room temperature for 20 hours. The solvent was concentrated under vacuum and the residue was partitioned between DCM (100 mL) and water (100 mL). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with DCM (100 mL). The combined organics extracts were concentrated in vacuo and the residue purified by chromatography using a Flashmaster apparatus (100 g silica cartridge) and using a DCM:Methanol 0-25% gradient over 40 min. The desired fractions were combined and concentrated under vacuum to give the impure title compound as a yellow oil (5.1 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: COc1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-methoxy-5-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 212-213° C.). MS(ES+) m/z 308 ([M+1]+, 100).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][N:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:24]/[N:25]5[CH2:29][C:28](=[O:30])[NH:27][C:26]5=[O:31])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN1CC(=O)NC1=O
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 50 %

Procedure:
The title compound (20 mg, 51%) was synthesized from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.1 mmol) and 1-aminoimidazolidine-2,4-dione (22.77 mg, 0.198 mmol) using the same procedure as described in the synthesis of example 37. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.05 (d, 1H), 8.70 (d, 1H), 8.32 (d, 1H), 8.12 (d, 2H), 7.98 (d, 1H), 7.87 (d, 1H), 7.77 (m, 1H), 4.83 (s, 2H), 4.54 (s, 2H), 2.40 (s, 3H). LCMS (method B): [MH]+=401.1, tR=1.64 min.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH3:20])=[CH:14][CH:13]=1>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:2][OH:3])[CH2:19][CH3:20])=[CH:14][CH:13]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Hydroxylamine hydrochloride (7.5 g, 108 mmol) and sodium acetate (8.9 g, 108 mmol) were added to 50 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(4-Fluorophenyl)propan-1-one (15 g, 98.6 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (50 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 16.4 g of the title compound. MS: (+) m/z 168.36 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C2C=CC(C([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=O)=CC=2)C=CC=CC=1.CO>C1(C)C=CC=CC=1>[OH:23][C@@H:24]1[CH2:32][C@H:27]([OH:28])[C@H:26]([CH2:30][CH2:29][OH:31])[C@H:25]1[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCC[C@@H]1[C@@H](CC[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](O)C[C@@H]1O
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A 1.5 M solution of diisobutylaluminum hydride in toluene (12.6 mL, 18.9 mmol) was added dropwise to a stirred solution of a compound [9a] (2.0 g, 3.5 mmol) in toluene (60 mL) at room temperature. The mixture was stirred for 3 hour at the same temperature. Methanol (50 mL) was added dropwise to the stirred mixture at −5-+5° C. and the cooling bath was removed. The mixture was stirred for 1 hours at room temperature, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 1:5 v/v) to obtain 1.0 g (73% yield) of the compound [12a]. 1H and 13C NMR are in agreement with the structure.