Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29])(=[O:4])=[O:3].[NH3:32]>CO>[NH2:32][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:29])([F:30])[F:31].[CH3:1][S:2]([OH:5])(=[O:4])=[O:3]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: N
Solvent: CO
Product: CS(=O)(=O)O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCN)c(C(F)(F)F)c3)cc21
Temperature: 120 °C

Procedure:
A mixture of 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy]propyl methanesulfonate (500 mg), and ammonia in methanol (7M, 10 ml) was heated at 120° C. under microwave conditions for 20 minutes. After removal of solvent under vacuum, the expected product 6-[4-(3-aminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile was obtained as methanesulphonic acid salt. 1H NMR (CD3OD) δ: 8.44 (s, 1H), 8.35-8.42 (m, 3H), 7.36 (d, 1H), 4.32 (t, 2H), 4.02 (s, 3H), 3.23 (t, 2H), 2.25 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)(O)=O.Br.[NH2:17][CH2:18][CH2:19][CH2:20][SH:21]>>[CH3:15][NH:14][C:11]1[CH:12]=[CH:13][C:5]2[CH:4]=[C:1]3[S:21][CH2:20][CH2:19][CH2:18][N:17]3[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: NCCCS
Reactant: CNc1ccc(CC(=O)O)c(C(=O)O)c1
Agent: Br
Product: CNc1ccc2cc3n(c(=O)c2c1)CCCS3

Procedure:
By following the same procedure as in Example 29 using 2.3 g. of 2-carboxymethyl-5-methylaminobenzoic acid and 1.8 g. of 3-aminopropanethiol.hydrobromide, 300 mg. of 8-methylamino-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(SCCCCl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SCCCCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a cooded (5° C.) solution of 1-chloro-3-(4-aminothiophenoxy)propane (4.9 g, 0.024 mol) and pyridine (2.1 g 0.027 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (3.1 g, 0.027 mol). The mixture was stirred at room temperature for 16 hours, washed with 2 N HCl, brine, dried (MgSO4), and concentrated. Recrystallization from EtOH gave 4.0 g (59%) of product as a pink solid m.p. 61°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.N1C2C(=CC=CC=2)CCC1.[CH3:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH2:34][CH2:33][CH2:32]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[C:7]([C:8]([N:35]2[C:36]3[C:31](=[CH:30][C:29]([CH3:28])=[CH:38][CH:37]=3)[CH2:32][CH2:33][CH2:34]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Agent: c1ccc2c(c1)CCCN2
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 1, Step 2, replacing 2-(3-trifluoromethyl-phenoxy)-nicotinic acid with 2-(3-chloro-phenoxy)-nicotinic acid (Example 3, Step 1) and 1,2,3,4-tetrahydro-quinoline with 6-methyl-1,2,3,4-tetrahydro-quinoline ([CAS RN 91-61-2]). MS (ISP): 379.1 [M+H]+.
Reaction SMILES: ClC(Cl)C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>O>[CH:32]1[CH:31]=[CH:30][N+:29]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[C@H:17]([NH:18][C:19]([CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:26])[C:16](=[O:27])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])=[CH:34][CH:33]=1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Reactant: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (0.1 g., 2.15 mmole.) was suspended in water (4 ml.), and pyridine (0.352 ml., 4.3 mmole.) was added. The solution was heated at 50° for 1 hour, acidified to pH 4.5 with acetic acid, and washed with ethyl acetate and finally with petrol. The aqueous solution was freed from dissolved organic solvents and applied to a column comprising (from top to bottom) layers of deactivated neutral alumina (8 ml.), Dowex 1 (AcO-) (20 ml.) and Zeokarb 226 (H+) (5 ml.). Elution with water was carried out until the eluate showed no optical rotation; the total eluate was freeze-dried and the residue triturated with methanol to give a white solid (296 mg.), [α]D23 +48.8° (c 0.8, water), λλmax (water) 238nm (E1cm1% = 351), 255 nm (E1cm1% = 324).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH:24](=O)[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])[CH:6]=2)[C:2]([CH3:23])([CH3:1])[CH2:3]1)[CH3:25]
Reactant: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Step B) (300 mg, 0.96 mmol) was treated with acetaldehyde (70 μL) and NaBH(OAc)3 (300 mg, 1.4 mmol) in CH2Cl2 (50 mL) overnight. After drying in vacuo, the reaction mixture was purified via flash chromatography on silica gel using EtOAc to afford the desired compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O.[BH4-].[Na+]>>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: O=Cc1ccccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(Cc4ccccc4F)C3)cc2)nc1
Yield: 42.9 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0305 g, 0.103 mmol), 2-fluoro-benzaldehyde (0.0160 mL, 0.152 mmol), and sodium borohydride (0.0093 g, 0.246 mmol) provide 0.0179 g (43%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25FN3O2 406.1931, found 406.1936; 1H NMR (CDCl3): 8.56 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.37 (dt, 1H, J=1.9, 7.3 Hz), 7.27-7.18 (m, 3H), 7.09 (dt, 1H, J=1.0, 7.3 Hz), 7.06-6.97 (m, 3H), 6.93 (dd, 1H, J=1.0, 8.8 Hz), 5.71 (s br, 2H), 3.56 (s, 2H), 3.04-2.97 (m, 1H), 2.93 (d, 1H, J=10.7 Hz), 2.85 (tt, 1H, J=3.4, 11.2 Hz), 2.12-2.01 (m, 2H), 1.96-1.88 (m, 1H), 1.81-1.64 (m, 2H), 1.41 (dq, 1H, J=4.4, 11.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:21][C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])[C@:10]([CH3:16])([C:12]([F:13])([F:14])[F:15])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Reactant: Cc1ccc(C(=O)CBr)cn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3C[C@@]2(C)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.97 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are added to a suspension of 141.94 mg (5.91 mmol) of sodium hydride in 20 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 872.32 mg (2.96 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF is added dropwise to the reaction medium at 0° C. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 150 mg of (S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:49]=[CH:50][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:34][C:35]=1[CH2:36][CH2:37]3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of 3.5 g of difluoromethyldiphenylphosphine oxide in 100 ml of tetrahydrofuran is slowly mixed with 7 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 2 g of 3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-trien-17-one in 50 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 1.3 g of 17-difluoromethylene-3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-triene is obtained as colorless crystals with a melting point of 90-91° C., [α]D22 =-9.2° (c=0.5% in pyridine).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: CN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(CCc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate (0.10 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.10 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.056 g of tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[C:20]1([S:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)CCC>>[CH3:15][S:16]([O-:19])(=[O:18])=[O:17].[CH2:25]([O:27][SH+:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CS(=O)(=O)O
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CCCCOc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCO[SH+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CS(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
7 g of phosphorus pentoxide and 70 g of methanesulfonic acid were mixed while stirring, dissolved and then stirred at room temperature. Thereto, 25 g (0.124 mol) of diphenyl sulfoxide and 20.4 g (0.136 mol) of n-butoxybenzene were added while stirring and stirred at 50° C. for 4 hours. The reaction solution obtained was poured into 500 ml of ice water, washed twice with 150 ml of toluene and rendered to be alkalescent by tetramethylammonium hydroxide, thereby obtaining an aqueous solution of butoxyphenyldiphenylsulfoniummethane sulfonate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[N+:29]([C:20]1[CH:21]=[C:22]([S:25](=[O:27])(=[O:26])[NH2:28])[CH:23]=[CH:24][C:19]=1[NH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][CH2:9]1)([O-:31])=[O:30]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl trans-4-(aminomethyl)cyclohexylcarbamate HCl (1.0 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.83 g) in tetrahydrofuran (5 mL) was added diisopropylethylamine (1.98 mL) and the reaction stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate (75 mL) and washed with saturated ammonium chloride (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting solid was triturated with dichloromethane (50 mL), filtered and dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35](=[O:36])[N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]2=[N:28]1)[C:25]#[CH:26].C#C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35](=[O:36])[N:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]4=[N:28]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1nc2ccccn2c1=O
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Agent: C#C
Solvent: O
Product: Cc1nnc2n1-c1ccc(C#CCn3nc4ccccn4c3=O)cc1C(c1ccccc1F)=NC2

Procedure:
This compound was obtained as described in example 17 by coupling of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 2-(2-propynyl)-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one. The product was purified by chromatography in the usual fashion and crystallized from ethyl acetate/ethanol. Recrystallization from ethanol gave light yellow crystals with m.p. 170°-173° C. They contained 0.66 molar amounts of water. The synthesis of the required acetylene is described in Example 27.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH3:26][CH:27]([NH2:30])[CH2:28][OH:29]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:30][CH:27]([CH3:26])[CH2:28][OH:29])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: CC(N)CO
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Solvent: CCO
Product: CC(CO)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and DL-2-amino-1-propanol (0.7 g) in 20 ml of ethanol was placed in a high-pressure reaction equipment and heated to 100° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 25:1) to give the desired product as a light yellow solid. MS: 470; 1H NMR (DMSO-d6, 300 MHz): δ 10.60 (brs, 1/2H, NH, D2O exchangeable), 9.69 (brs, 1/2H, NH, D2O exchangeable), 9.22 (brs, 1/2H, NH, D2O exchangeable), 8.55 (s, 1H, OH, D2O exchangeable), 7.91 (brs, 1/2H, NH, D2O exchangeable), 7.70 (brs, 1/2H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 5.09 (brs, 1H, OH), 3.80 (m, 1H, CH), 3.49 (m, 1H, CH). 3.44 (m, 1H, CH), 1.15 (d, 3H, J=6.3 Hz, CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH:21]=[N:20][N:19]=[C:18]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[CH2:28]=O.Cl.[CH3:31][NH:32][CH3:33]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:17]2[C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:19][N:20]=[C:21]2[CH2:31][N:32]([CH3:28])[CH3:33])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: C=O
Reactant: CNC
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(CN(C)C)nnc3-c3cccnc3)c2nc1OC
Yield: 65.2 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-[3-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 98, 101 mg, 0.25 mmol), paraformaldehyde (15 mg, 0.5 mmol) and dimethylamine hydrochloride (22 mg, 0.27 mmol) in acetic acid (5 mL) was heated under reflux for 5 hours. After being cooled, the mixture was concentrated under reduced pressure, water (20 mL) was added, the solution basified with aqueous potassium carbonate solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 95:5, by volume) to afford the title compound (75 mg, 65%) as a white solid, mp 192-194° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (1.0 g, 3.34 mmol) and morpholine (1.16 mL, 13.3 mmol) was added tetraisopropyl-orthotitanate (3.95 mL, 13.3 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (30.0 mL) and sodium cyanoborohydride (930 mg, 13.3 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with hexane/ethyl acetate/triethylamine 40:10:1 to give rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-morpholine (650 mg, 52%) as a yellow solid, MS: m/e=371.3 (M+H+).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([Br:18])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:17])[CH3:16])(=O)C.ClCCl.ClC1C=[C:25](C=CC=1)[C:26]([O:28]O)=[O:27].C(OCC)(=O)C>CCCCCC>[C:26]([O:28][C:4]1[CH:5]=[C:6]([Br:18])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]2([CH3:16])[CH3:17])(=[O:27])[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Oc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.9 %

Procedure:
A solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 15A, 1.3 g, 4.18 mol) in anhydrous dichloromethane (30 mol) was treated with a 77% aqueous solution of 3-chloroperoxybenzoic acid (5.75 g, 33.44 mmol) and the resulting reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was then cooled in an ice bath and cautiously quenched with saturated sodium thiosulfate solution. The phases were separated and the organic phase was washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that on flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title compound as an oil (1.3 g, 92%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2C=[C:18]([C:26]#[N:27])[C:19]3[N:23]=[N:22][N:21]([CH3:24])[C:20]=3[CH:25]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29])(=O)=O.Cl.[CH3:33][C:34]1([OH:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C[N:42]1C(=O)CCC1>>[OH:40][C:34]1([CH3:33])[CH2:39][CH2:38][N:37]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:25]=[C:20]4[N:21]([CH3:24])[N:22]=[N:23][C:19]4=[C:18]([C:26]#[N:27])[N:42]=3)=[CH:12][C:11]=2[C:28]([F:29])([F:30])[F:31])[CH2:36][CH2:35]1
Reactant: CC1(O)CCNCC1
Reactant: Cn1nnc2c(C#N)cc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: CN1CCCC1=O
Agent: Cl
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCCN4CCC(C)(O)CC4)c(C(F)(F)F)c3)cc21
Temperature: 100 °C

Procedure:
A mixture of 3-(4-(4-cyano-1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-(trifluoromethyl)phenoxy)propyl methanesulfonate (100 mg) and 4-methylpiperidin-4-ol hydrochloride (166 mg) in NMP (2 ml) was heated at 100° C. under microwave conditions for 30 minutes. The mixture was purified by HPLC to give the expected product (9.4 mg). 1H NMR (CD3OD) δ: 8.55 (s, 1H), 8.35-8.42 (m, 2H), 7.32 (d, 1H), 4.44 (s, 3H), 4.25 (t, 2H), 2.76-2.89 (m, 4H), 2.63-2.75 (m, 2H), 2.13 (quin, 2H), 1.64-1.80 (m, 4H), 1.24 (s, 3H). MS m/z 475 (M+H).