Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.Cl.[CH3:24][NH:25][CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:19]([N:25]([CH3:26])[CH3:24])=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CNC
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Agent: Cl
Product: CN(C)C(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid (0.1 g) was reacted with N,N-Dimethylamine Hydrochloride similarly to the conditions described in Example 2 to produce 10-bromo-N3,N3-dimethyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. This intermediate was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 21 mg (16%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3,N3-dimethyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:28])[CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:26][CH3:27])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: CCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1c(Cl)cccc1N1CCNCC1
Yield: 78.5 %

Procedure:
To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])=[N:17][C:4]=2[CH:3]=1.[CH3:35][N:36](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]2[C:5]3[N:15]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:16]([CH:18]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:19])=[N:17][C:4]=3[CH:3]=[C:2]([C:35]#[N:36])[N:7]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: CC(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 140 °C

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (400 mg, 0.80 mmol) in DMF (16 mL) was added zinc cyanide (37.7 mg, 0.32 mmol), and the reaction was deoxygenated by purging with nitrogen for 10 minutes. 1,1-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (65.5 mg, 0.08 mmol) was added, and the reaction mixture was again deoxygenated for 5 minutes. The reaction was heated to 140° C. for 5 h under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chormatography (eluting with 35% EtOAc/petroleum ether) to yield 4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calcd. for C27H26ClFN6 [M+H]+ 489. found 489.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid (Step 20.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine (Step 15.1). Title compound: ES-MS: 522.0 [M+H]+; single peak at tR=3.15 min (System 1); Rf=0.19 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[NH2:48][C:49]1[C:50]([C:54](O)=[O:55])=[N:51][O:52][N:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:48][C:49]1[C:50]([C:54]([N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]3[CH:30]=[CH:31][C:32]4[NH:33][C:34]5[N:35]=[C:19]([NH:20][C:21]6[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=6)[CH2:26][CH2:27][C:28]=3[CH:36]=4)[N:18]=[CH:17][C:16]=5[Cl:15])=[O:46])[CH2:41][CH2:42]2)=[O:55])=[N:51][O:52][N:53]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Nc1nonc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nonc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-amino-1,2,5-oxadiazole-3-carboxylic acid as starting materials in 41% yield. LCMS for C27H28ClN10O3 (M+H)+: m/z=575.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:29])[C:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]=O)([CH3:18])[CH3:17])[CH3:13].N1CCCC1>CO>[CH2:12]([O:14][C:15](=[O:29])[C:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1/[CH:27]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:18])[CH3:13]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To the mixture of 6-chlorooxindole (5.3 g, 31.7 mmol) and 2-(4-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (8 g, 31.7 mmol) in methanol (30 mL) was added pyrrolidine (2.6 mL, 31.7 mmol) dropwise. Then the mixture was heated at 70° C. for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (10 g).
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[CH3:16][O-:17].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:16][O:17][C:12]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole(1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., solid sodium methoxide (4 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-methoxy-6-nitro-1H-indazole as a brown solid, which was reduced to 3-methoxy-1H-indazol-6-ylamine by hydrogenation following general procedure F.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:13][C:14]2[C:22]3[N:21]=[C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[N:19]([CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:47]1([CH2:53][CH2:54][CH2:55]Br)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH:8]1([O:13][C:14]2[C:22]3[N:21]=[C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[N:19]([CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH2:55][CH2:54][CH2:53][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH2:37][CH2:36]4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrCCCc1ccccc1
Reactant: Clc1ccc(OCc2nc3c(OC4CCCC4)cccc3n2CCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2nc3c(OC4CCCC4)cccc3n2CCCC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][OH:20])=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(CO)n2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-hydroxymethyl-[1,2,4]triazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (from Step 2 above, 0.181 g, 0.641 mmol) and triethylamine (0.134 mL, 0.961 mmol) in dichloromethane (5 mL) at 0° C. was added methanesulfonylchloride (0.055 mL, 0.705 mmol). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to yield the desired product as a light yellow oil that was used without further purification.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH:41][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of the product from Example AB ((S)-2-[(azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid) (0.50 g, 1.95 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.63 g, 1.95 mmol) were coupled according to the procedure described in Example AH. The crude reaction product was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white foam, mp=53-57° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH2:17][CH2:18][C:19](N2C3C=CC=CC=3N=N2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:19](=[O:20])[CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCc1ccccc1)n1nnc2ccccc21
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CCc1ccccc1)c1c[nH]c2ccc(Br)cc12
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 5-bromoindole (1.0 g) in methylene chloride (10 ml), 1-(3-phenylpropanoyl)-1H-1,2,3-benzotriazole (1.28 g) was added. While stirring under ice cooling, a solution of titanium(IV) chloride (1.11 ml) in methylene chloride (5.0 ml) was added and the mixture was stirred at room temperature for 5 days. To the reaction solution, ice water (50 ml) was added, the mixture was stirred for a while, then the organic layer was separated and successively washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=19:1 to 4:1) to afford the above-identified compound (1.22 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]3[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(NC2CCNCC2)nn1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a mixture of 6-(piperidin-4-ylamino)-pyridazine-3-carbonitrile (D3) (0.15 g, 0.7 mmol) and α,α,α-trifluoro-p-tolualdehyde (0.15 ml, 1.1 mmol) in dichloromethane (2 ml), was added sodium triacetoxyborohydride (0.232 g, 1.1 mmol) and acetic acid (0.041 ml). The reaction mixture was then stirred at room temperature for 18 h. A saturated solution of sodium hydrogen carbonate was then added and the organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by HPLC. The desired fractions were collected and the solvent was evaporated in vacuo to yield E7 (0.101 g, 38%) as a solid. C18H18F3N5 requires 361. Found 362 (MH+); mp: 243.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[C:11]([C:12]([OH:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: NS(=O)(=O)O
Reactant: COc1c(C=O)ccc2c1CCC2
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)O)ccc2c1CCC2
Temperature: 26.5 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a clear solution of 4-Methoxy-indan-5-carbaldehyde (11.5 gm, 0.065 mole) in Dichloromethane (100 ml), Sulphamic acid (19.0 gm, 0.196 mole) was added at 25-28°. A solution of Sodium chlorite (15.28 gm, 0.169 mole) in water (50 ml) was added at 5-10° C. The reaction mixture was stirred for 5 hours at 25-28° C. Finally the reaction mixture was poured into water (200 ml) and extracted with Dichloromethane (2×200 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give 12.0 gm of desired product as a viscous oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1>>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC(F)(F)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 3,3-difluoroazetidine to give 221. MS: (ESI+)=389.0
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:10][NH2:11])=[O:9].[CH2:12]([N:16]=[C:17]=[O:18])[CH:13]([CH3:15])[CH3:14].C(OCC)C>C1COCC1>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:10][NH:11][C:17]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:18])=[O:9]
Reactant: Cc1csc(C(=O)NN)c1Cl
Reactant: CC(C)CN=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(C(=O)NNC(=O)NCC(C)C)c1Cl
Reaction time: 8 h

Procedure:
1.00 g (5.25 mmol) of 3-chloro-4-methylthien-2-ylcarboxylic acid hydrazide are placed in 10 ml THF at room temperature. 520 mg (5.25 mmol) of isobutyl isocyanate, dissolved in 2 ml THF, are rapidly added dropwise with stirring. The mixture is further stirred overnight at room temperature. For the workup, the reaction mixture is treated with 10 ml diethyl ether, cooled in the water/ice-bath to about 0° C., and the resulting precipitate recovered by filtration, washed with diethyl ether and dried in vacuo. 1.29 g (85% of theory) of the target compound are thus obtained.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>C1COCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (60.83 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (5% MeOH, 95% CHCl3) providing the title compound in 50% yield (75 mg, 0.155 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[H-].[Na+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:11]([O:1][CH2:2][C:3]([CH2:8][O:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])([CH2:6][O:7][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH2:4][OH:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(CO)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 22.5 %

Procedure:
To pentaerythritol (1.5 g, 11.0 mmol) were added DMF (100 ml), 1-bromooctadecane (11.4 g, 34.2 mmol) and sodium hydride (60 wt %, 1.54 g, 38.5 mmol), and the mixture was stirred at 100° C. for 22 hr. The reaction mixture was cooled to room temperature, chloroform (150 ml) was added, and 1N hydrochloric acid (150 ml) was added further dropwise. After stirring, the aqueous layer was removed, and the organic layer was further washed with 1N hydrochloric acid (100 ml) and water (100 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with methanol (150 ml), and the obtained precipitate was washed with methanol (150 ml). The crude crystals were dried and purified by silica gel column chromatography (hexane:chloroform=1:1→hexane:ethyl acetate=10:1) to give 2,2,2-tris(octadecyloxymethyl)ethanol (2.21 g, 2.47 mmol, yield 23%).
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][N:10]=1.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:34]=[N+:35]=[N-:36])=[CH:11][N:10]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Reaction time: 3 h
Yield: 99 %

Procedure:
Into ethyl acetate was suspended 1.91 g of 6-(trifluoromethyl)nicotinic acid, and then 1.52 g of triethylamine and 3.03 g of DPPA were added thereto, followed by 3 hours of stirring. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and saturated saline and the solvent was removed by evaporation to obtain 2.0 g of 6-(trifluoromethyl)nicotinyl azide as a solid. The resulting acid azide was dissolved into 20 ml of toluene and the solution was heated and refluxed to convert the acid azide into 5-isocyanato-2-(trifluoromethyl)pyridine. Thereafter, 1 ml of methanol was added thereto at room temperature, followed by 1 hour of stirring. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation to obtain 1.2 g of the title compound.