Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>O1CCCC1.O>[C:3]([CH:5]=[CH:14][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:4]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.4 g (10.4 mmol) of sodium hydride (washed three times with hexane) in 2 mL of tetrahydrofuran was added 1.6 mL (10.4 mmol) of diethyl cyanomethylphosphonate. The mixture was stirred at ambient temperature for 15 minutes. To the mixture was added a solution of 3.0 g (8.7 mmol) of material from Example 45 in 15 mL of tetrahydrofuran. After stirring for two hours, the mixture was diluted with 25 mL of water and extracted three times with 20 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1CC#N
Yield: 72.5 %

Procedure:
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100° C. for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O>ClCCl>[Cl:24][C:4]1[C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]([C:14]([F:15])([F:16])[F:17])[O:9]2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Solvent: ClCCl
Product: CCc1c(O)cc2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a mixture of 100 mg (0.35 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 5 mL of anhydrous dichloromethane was added dropwise a solution of 0.42 mL (1.0 M in dichloromethane, 0.42 mmol) sulfuryl chloride. The resulting solution was stirred at room temperature for one hour. The sample was concd and the residue purified on a silica gel column with ethyl acetate:hexane: acetic acid to give 60 mg (52%) of a light yellow solid: 1H NMR(CDCl3/400 MHz) 7.71(s, 1H), 6.71(s, 1H), 5.99(s, 1H), 5.65(q, J=6.0 Hz, 1H), 2.38(m, 1H), 2.06(m, 1H), 0.84(t, J=7.6 Hz, 3H); MS (ESI+) 323.0 (M+1, 100); LCMS (ES−) 321 (M−H, 100); HRMS (ES−) m/z calcd for (M−1; C13H9ClF3O4) 321.0136, found 321.0118.
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.O>C1COCC1>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of Z-N-Me-Val-OH (700 mg, 2.64 mmol), N-Me-Tyr(3-tBu)-NH2 (0.55 g, 2.20 mmol) and CMPI (674 mg 2.64 mmol) in THF (22 ml), under cooling with ice, TEA (0.61 ml) was added and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=3:2) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.98 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1>ClCCl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:33][CH:34]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reaction time: 1 h

Procedure:
A flask was charged with tert-butyl 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-cyanophenyl)propanoate (0.098 g) in 1 ml of dichloromethane and 1 ml of TFA, and the reaction was stirred for 1 hour. The reaction was concentrated and dried under vacuum. Isolated 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl) propanoic acid (0.080 g). MS +449.1 [M+1].
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:1]([NH:8][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([F:9])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1F
Temperature: 0 °C

Procedure:
Benzylamine (7.6 mL, 69 mmol) in 30 mL THF was added to ethyl 2,4-difluoro-5-nitro-benzoate (16.0 g, 69 mmol) in 270 mL THF with TEA (19.7 mL, 140 mmol) under stirring at 0° C. The mixture was stirred for 3.5 h at ambient temperature. The mixture was concentrated i.vac., the residue stirred with water, filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1>>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: [(S)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester and 1-bromo-3,5-difluorobenzene.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].Cl>O1CCCC1.C(OCC)(=O)C>[OH:34][C:30]1([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][C:27]1[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: COc1cccc(CC2CCCC2=O)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-diphenyloxazole in tetrahydrofuran (100 ml) at -78° C. under nitrogen was added n-butyllithium (in hexane, 1,7N, 12 ml). After 30 minutes, at the same temperature a solution of 2-(3-methoxybenzyl)cyclopentanone (3.8 g) in tetrahydrofuran (10 ml) was added dropwise thereto. After being stirred for 1 hour at 0° C., the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and 1N-hydrochloric acid (50 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed (n-hexane--ethyl acetate:5:1-2:1) on silica gel to afford 1-hydroxy-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentane (8.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:30][CH:29]([CH3:32])[CH3:31])[C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(C)C)cn2)cc1
Yield: 17.1 %

Procedure:
The title compound (7.6 mg) was prepared from 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (39 mg, 0.097 mmol) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.020 mL, 0.097 mmol) in acetonitrile (2 mL), following the procedure described for Example 1. LCMS (2 min, formic) Rt 1.37 min, m/z (ES+) 458 (M+H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.CN(C1C=CC=CN=1)C.[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)[CH3:38]>C1(C)C=CC=CC=1>[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45]([O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:26])([F:27])[F:16])=[CH:24][CH:23]=2)=[O:46])[CH2:41][CH2:40]1)[CH3:38]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
First, 4.6 g of dicyclohexylcarbodiimide in 80 ml of toluene are added to a mixture of 4 g of 4-trifluoromethoxyphenol and 20 ml of toluene, 0.2 g of dimethylaminopyridine is then added, the mixture is stirred at room temperature for I hour, and 3.8 g of trans-4-ethylcyclohexanecarboxylic acid are then added. After work-up and purification by chromatography and/or crystallization, 4-(trifluoromethoxy)phenyl trans-4-ethylcyclohexanecarboxylate is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[O:6][CH2:5][CH2:4][O:3]1.[CH3:12][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:10][C:9]([OH:11])([CH2:8][CH2:7][C:2]1([CH3:1])[O:3][CH2:4][CH2:5][O:6]1)[CH3:12]
Reactant: C[Mg]Br
Reactant: CC(=O)CCC1(C)OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCC1(C)OCCO1
Reaction time: 0.67 h

Procedure:
The obtained 4-(2-methyl[1,3]dioxolan-2-yl)butan-2-one (27.60 g) was dissolved in tetrahydrofuran (220 ml), and thereafter, methylmagnesium bromide (3 M tetrahydrofuran solution; 85 ml) was added to the solution at a room temperature. The obtained mixture was stirred for 40 minutes, and an aqueous saturated ammonium chloride solution (300 ml) was then added thereto, followed by extraction with ethyl acetate (300 ml×3). The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate-hexane (1:1)) to obtain 2-methyl-4-(2-methyl[1,3]dioxolan-2-yl)butan-2-ol (21.18 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light brown solid (92 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[CH:24](O)=O.N>CO.O>[CH3:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: c1ccc(-c2sc3ccccc3c2N2CCNCC2)cc1
Reactant: O=CO
Agent: C=O
Agent: N
Solvent: O
Solvent: CO
Product: CN1CCN(c2c(-c3ccccc3)sc3ccccc23)CC1

Procedure:
A mixture of 7.0 g (24 mmole) of 3-(piperazino)-2-phenyl-benzo(b)thiophene, 3.5 milliliters of formalin at 35% (41 mmole) and 3.5 milliliters of formic acid at 98-100% (92 mmole) is refluxed for 1 hour. After cooling, it is poured into water, made alkaline with ammonia and extracted with CH2Cl2. By evaporating the organic phase dried over K2CO3, 7.2 g (98% of theory) of 3-(4'-methylpiperazino)-2-phenyl-benzo(b)thiophene are obtained: beige crystals, mp 118°-120° (methanol).
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:29])[CH2:25]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[C:14]([C:15]3[NH:17][C:18]4[C:19]([C:24](=[O:29])[CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)CC(=O)c1ccccc1N
Reactant: O=Cc1cccnc1SCc1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=c1cc(-c2cccnc2SCc2ccccc2)[nH]c2ccccc12
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
2-[(Phenylmethyl)thio]pyridine-3-carboxaldehyde (6.01 g, 26.2 mmole, 1 equiv.), 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (5.17 g, 26.2 mmole, 1 equiv.), and piperidine (1.3 ml, 13.1 mmole, 0.5 equiv.) were combined in toluene (240 ml), and the mixture was heated to reflux under a Dean - Stark trap. After 3.5 hr, the reaction was concentrated to one half volume and cooled in the refrigerator overnight. Filtration of the mixture gave 2-[2-[(phenylmethyl)thio]-3-pyridinyl]-4(1H)-quinolinone (2.37 g, 26%) as a pale yellow solid: mp 219-226 (dec); TLC (50% EtOAc/CHCl3) Rf 0.19; 1H NMR (DMSO-d6) δ11.93 (br s, 1 H), 8.67 (dd, J=4.8, 1.8 Hz, 1 H), 8.10 (dd, J=8.1, 1.1 Hz, 1 H), 7.87 (dd, J=7.7, 1.8 Hz, 1 H), 7.60-7.72 (m, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.17-7.45 (m, 7 H), 6.06 (br s, 1 H), 4.44 (s, 2 H); IR (KBr) 2100-3300 (br), 1633, 1595, 1573, 1549, 1534, 1502, 1474, 1440 cm-1 ; MS (NH3), m/e (%) 345.0 (100, (M+H)+), 255.1 (22.7), 253.1 (20.7). Anal. Calcd for C21H16N2OS: C, 73.23; H, 4.68; N, 8.13; S, 9.31. Found: C, 72.98; H, 4.56; N, 8.03; S, 9.20.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[CH2:15][CH:7]2CN[CH2:10]1)([O-])=O.[CH2:16](N(CC)CC)[CH3:17].C(Cl)Cl.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:16][CH:17]=[CH:5][CH:4]=[CH:14][CH:13]=[CH:12][CH2:6][CH2:7][CH2:15][CH2:11][CH3:10]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC=CC=CC=CCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
In a 30 ml reaction vial 4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (195 mg, 0.955 mmol), Triethylamine (0.40 mL, 2.9 mmol) were charged to methylene chloride (10 mL, 200 mmol). The reaction was cooled to 0° C. and the methanesulfonyl chloride (81 uL, 1.0 mmol) added dropwise with a syringe. The reaction was allowed to stir at 0° C. for 30 minutes. The reaction was poured into water (20 ml) and saturated sodium bicarbonate solution (20 ml) and the layers separated. The aqueous was washed with another 2×10 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield 10-methanesulfonyl-4-nitro-10-aza tricycle[6.3.1.0*2,7*]dodeca-2,4,6-triene (170 mg, 63%) as a brown oil that was used crude in the next reaction. 1H-NMR (CDCl3) δ 8.17 (d, J=6.1 Hz, 1H), 8.13 (s, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.77-3.68 (m, 2H), 3.41-3.28 (m, 4H), 2.52-2.42 (m, 1H), 2.30 (s, 3H), 1.92 (d, J=11.1 Hz), LC/MS (ESI+): 283 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:26]=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(F)c(F)c2)n1
Temperature: 150 °C
Yield: 48 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 3,4-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.033 g (48% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C1COCC1.O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,4-dichlor-[1,3,5]triazine (2.25 g, 15 mmol; WO 2004/072063, Expl. 9) in 20 ml of THF, MeNH2 (15 ml of 2 M solution in THF) is added. After 1 h the mixture is diluted with 15 ml of water and concentrated partially in vacuo. The precipitated title compound can be filtered off, washed with ice-water and dried: ESI-MS: 143 [M−H.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCNC2
Yield: 79 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (167 mg, 0.34 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (124 mg, 79%) as a yellow solid: mp 226-231° C.; 1H NMR (500 MHz, CD3OD) δ 8.89 (d, J=5.4 Hz, 1H), 8.61 (overlapping ddd, J=8.0, 1.6 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.02 (overlapping dd, J=6.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.44 (dd, J=7.6, 2.7 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.57 (s, 2H), 4.56 (s, 2H), 3.73 (s, 3H), 3.60 (t, J=6.0, 2H), 3.13 (t, J=6.0, 2H); ESI MS m/z 387 [M+H]+; HPLC (Method B) 98.6% (AUC), tR=9.2 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=O)[CH3:10])=[CH:5][CH:4]=1.B.CSC.Cl>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH2:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NCc1ccc(C(F)(F)F)cc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCNCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
N-[4-(trifluoromethyl)benzyl]acetamide (3.085 g, 14.204 mmol) was dissolved in THF (100 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (2.698 g, 35.511 mmol) was added and the mixture was refluxed over night at RT. HCl (15 ml, 10%) was gently added and was stirred overnight. The solvent was removed by evaporation Diethyl ether (20 ml) was added and the product was extracted to the water phase by K2CO3 (3×15 ml), the water phase was acidified by HCl (10 ml, 10%) and the product was extracted to the organic phase by EtOAc (3×15 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.809 g of N-[4-(trifluoromethyl)benzyl]ethanamine (yield 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=CC=[CH:4][C:3]=1NN.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH2:31][CH2:32]O)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([C:31]3[CH:32]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccccc1Cl
Product: COc1ccc(C2=NN(c3ccc(Cl)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from 2-chlorophenylhydrazine and compound C as described for compound 35. M.p. 140°-141° C.
Reaction SMILES: [N:1](=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([OH:8])=O)[OH:2].Cl.Cl.[CH:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])[CH3:18]>>[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([C:6](=[O:8])[CH2:5][CH2:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:1][OH:2])[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)CCC(=NO)c1ccccc1
Agent: Cl
Product: CC(C)N1CCN(C(=O)CCC(=NO)c2ccccc2)CC1

Procedure:
Using coupling method A, 4-hydroximino-4-phenylbutyric acid (500 mg, 2.6 mmol) and 1-isopropylpiperazine dihydrochloride (521 mg, 2.6 mmol) afforded, after purification (SiO2: 10% isopropylamine in EtOAc), 730 mg (89%) of the title compound.