Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[CH:10]3[O:12][CH:11]3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([OH:12])[C@H:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 22 h

Procedure:
6-Acetyl-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (0.33 g, prepared as described in Example 1 of U.K. Pat. No. 1,511,187), and 2-pyrrolidone (0.15 g), were stirred in dimethylsulphoxide (25 ml) under nitrogen at room temperature. Sodium hydride (0.05 g, 80%) was added during 2 mins and the reaction stirred for a further 22 hours. Addition of water, extraction with ethyl acetate, drying of the organic layer with magnesium sulphate, filtration, evaporation and recrystallisation from ethyl acetate gave the title compound (0.04 g) of m.p. 218°-219°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cncc(F)c3)c2)c1=O
Yield: 59 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine, in the same way as in Example 1, to give 1-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one as an off-white solid (62 mg, 59%): δH (400 MHz, d6-DMSO) 3.69 (3H, s), 6.36 (1H, s), 7.23 (1H, d, J 7), 7.40-7.56 (3H, m), 7.68-7.69 (1H, m), 7.94 (1H, s), 8.57 (1H, d, J 3), 8.66 (1H, d, J 1); m/z (ES+) 339 [MH+].
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[O:15]C)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[C:28]([S:34]([CH2:37][C:3]([C:5]2[N:6]=[C:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:4])(=[O:35])=[O:36])[CH:27]=1
Reactant: COC(=O)c1nc(Cc2ccc(F)cc2)c2ccccc2c1OC
Reactant: CNc1ccc(Cl)cc1S(C)(=O)=O
Product: CNc1ccc(Cl)cc1S(=O)(=O)CC(=O)c1nc(Cc2ccc(F)cc2)c2ccccc2c1O

Procedure:
2-(5-Chloro-2-methylamino-benzenesulfonyl)-1-[1-(4-fluoro-benzyl)-4-hydroxy-isoquinolin-3-yl]-ethanone (36a) was prepared from 1-(4-fluoro-benzyl)-4-methoxy-isoquinoline-3-carboxylic acid methyl ester and (4-chloro-2-methanesulfonyl-phenyl)-methyl-amine as described in steps 1-4 of Example 8.
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C(C)C)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (0.3 g, 0.67 mmol) and 4-isopropyl-phenylboronic acid (0.24 g, 1.0 mmol) in toluene (16 mL) and EtOH (4 mL) is added 2 M K2CO3 (0.6 mL, 1.34 mmol). The mixture is purged with argon for 30 minutes. Pd(PPh3)4 (0.077 g, 0.067 mmol) is added and the mixture is heated at 100° C. overnight. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth. The filtrate is diluted with water (30 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash using 24 g redisep column) eluting with 45% EtOAc/hexane to give the title compound as a brown liquid (0.22 g, 68.75%). LCMS m/z 481 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>ClCCl>[ClH:27].[ClH:27].[N:11]1([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cnccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(c1ccc2cnccc2c1)N1CCNCC1

Procedure:
150 mg of 6-(4-tert-butoxycarbonylpiperazin-1-ylsulfonyl)isoquinoline was dissolved in 10 mL of dichloromethane, and 1 mL of 4 M hydrochloric acid-dioxane solution was added dropwise thereto with stirring and then reacted at room temperature for 3 hours. From the reaction solution, the solvent was distilled off, and the obtained residue was dissolved in 0.5 mL of methanol. Then, 5 mL of ethyl acetate was added with vigorous stirring, and the deposited white crystal was collected by filtration and dried to obtain 35 mg of the compound of interest as a white crystal (25%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]3=[O:32])=[CH:17][C:16]=2[F:33])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:34]([CH2:26][C@@H:24]1[O:23][C:22](=[O:32])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:13]3[CH:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[N:11]=[CH:12]3)=[C:16]([F:33])[CH:17]=2)[CH2:25]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
(5R)-3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (13.6 g) was dissolved in dry N,N-dimethylformamide (110 ml). Sodium azide (3.53 g) was added, and the mixture was heated at 80° C. for 3.5 hours. The mixture was cooled, diluted with water (1.1 L) containing sodium bicarbonate (2 g), and extracted with ethyl acetate (2×800 ml). Combined organics were washed with water (2×300 ml), then brine, and dried over magnesium sulfate. The solution was evaporated to a small volume (˜100 ml), and insolubles filtered. The ethyl acetate soluble material was columned on silica (100 g), eluting with ethyl acetate. Product fractions were combined and evaporated to give a gum (10.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9].[CH3:13][OH:14]>>[C:8]([C:6]1[C:5]([C:11]([OH:10])=[O:12])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)([O:14][CH3:13])=[O:9]
Reactant: CO
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Product: COC(=O)c1nc(C)ccc1C(=O)O

Procedure:
48.9 g of 6-methylpyridine-2,3-dicarboxylic anhydride in 200 ml of methanol are refluxed for 3 hours while stirring. Evaporating down the mixture under reduced pressure gives 57.9 g of the title compound of melting point 133°-158° C. (decomposition).
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH:14]=[O:15])=[C:7]2[C:11]([OH:13])=[O:12].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:28]([NH:47][C:48]1[S:49][CH:50]=[C:51](/[C:53](=[N:57]/[O:58][CH3:59])/[C:54](Cl)=[O:55])[N:52]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(#N)C.C(Cl)Cl>[OH:15][CH:14]1[C:6]2[CH2:5][S:4][CH:3]3[CH:2]([NH:1][C:54](=[O:55])[C:53]([C:51]4[N:52]=[C:48]([NH:47][C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[S:49][CH:50]=4)=[N:57][O:58][CH3:59])[C:9](=[O:10])[N:8]3[C:7]=2[C:11](=[O:13])[O:12]1
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C3=C(CSC12)C(O)OC3=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
10 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 200 ml of acetonitrile: methylenchloride (1:1) are treated with 37.4 ml of N,O-bis(trimethylsilyl)acetamide at room temperature within ca. 5 minutes. After ca. 30 minutes the reaction mixture is cooled to −10° and 21 g of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid chloride are added in 3 portions. The temperature raises to −5°. After ca. 45 minutes the reaction mixture is treated with 4 ml of water. The temperature raises to 20°. The reaction mixture is stirred for ca. 10 minutes and filtered. 15 g of active charcoal are added to this filtrate and stirring is continued for ca. 10 minutes. After filtration the solvent of the filtrate obtained is evaporated. The evaporation residue is treated with tert.butyl-methyl ether. A crystalline, almost colourless precipitate is obtained, filtered off and dried. Crystalline N-(1,4,5a,6-Tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid amide is obtained in form of a diastereomeric mixture in the ratio of ca. 1:1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CCC#N)=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Cyanoethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 16; 47 mg, 0.1 mmol) is dissolved in 0.5 ml dioxane. After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (15 μl, 15 mg, 0.1 mmol), the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with 1 N hydrochloric acid and extracted with ethyl acetate. After drying with magnesium sulfate and evaporating off the solvent, the residue is purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH3:14])=[O:12])=[CH:7][C:6]=12.[F:23][C:24]1[C:25]([NH2:39])=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:39][C:25]1[N:26]=[CH:27][C:28]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([C:11]([N:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)[CH3:14])=[O:12])=[CH:7][C:6]=23)=[CH:29][C:24]=1[F:23]
Reactant: CN(C(=O)c1ccn2ncc(Br)c2c1)c1ccc(C#N)cc1
Reactant: CC1(C)OB(c2cnc(N)c(F)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C(=O)c1ccn2ncc(-c3cnc(N)c(F)c3)c2c1)c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 37 %

Procedure:
A mixture of 3-bromo-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide (I-8; 400 mg, 1.10 mmol 1.0 eq), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (I-37, 550 mg, 2.20 mmol 2.0 eq) and 1N Na2CO3 solution (4.0 mL) in 1,4-dioxane (10 mL) was degassed with argon gas for 10 min. Subsequently, tetrakis(triphenyl phosphine)-palladium(0) (250 mg, 0.22 mmol 0.2 eq) was added and the reaction mixture was stirred in a sealed tube at 100° C. for 2.5 h (cf. general Suzuki Procedure F). The solvent was removed under reduced pressure. Purification by silica gel chromatography, eluting with 5% MeOH/CH2Cl2 provided 79 as the desired product (37%). 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=7.0 Hz, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.78 (d, J=8.8 Hz, 3H), 7.53 (d, J=8.30 Hz, 2H), 7.46 (d, J=12.3 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 6.30 (s, 2H), 3.45 (s, 3H); ESI-LC/MS (m/z): [M+H]+ 387.10, RT 1.71 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[CH:40]=[N:39][CH:38]=1>ClCCl>[N:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[C:45]([NH:46][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:47]=[CH:48][CH:49]=2)[CH:40]=[N:39][CH:38]=1
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Reactant: Nc1cccc(-c2cncnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1[nH]c2c(C(=O)Nc3cccc(-c4cncnc4)c3)cccc2c1C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and 1-hydroxybenzotriazole (81 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg), and the mixture was stirred for 5 minutes. After adding 3-(pyrimidin-5-yl)aniline (94 mg) and 4-dimethylinopyridine (92 mg), the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-(3-(pyrimidin-5-yl)-phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (117 mg, 68.4%).
Reaction SMILES: [NH2:1][C:2]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:5]([CH2:6][C@@H:7]([CH2:23][C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:28][CH2:27]2)=[O:25])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1Br>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:30][CH2:31]2)=[O:25])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])=[CH:44][C:45]=1[C:46]([F:49])([F:48])[F:47]
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Br)c(N)c(C(F)(F)F)c3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3ccc(N)c(C(F)(F)F)c3)CC2)CC1
Reaction time: 3 h

Procedure:
100 mg 10% Pd/C were added to a solution of 150 mg (0.2 mmol) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione in 20 mL MeOH and the reaction mixture was hydrogenated at 50 psi H2 for 3 h at RT. The catalyst was suction filtered, the solvent was evaporated down i.vac., the residue was combined with 5% K2CO3 solution and EtOAc, the organic phase was separated off and evaporated down i.vac. The residue was triturated with diisopropylether and suction filtered.
Reaction SMILES: O.[C:2](=[O:5])([O-])[O-:3].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]#[N:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:47]([C:17]1[CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=2)[N:21]2[N:22]=[C:23]([NH:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:2]([OH:3])=[O:5])=[O:35])[N:24]=[C:20]2[N:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=2)[C:18]=1[CH3:46])#[N:48]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(NC(=O)c3ccccc3C(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 55 °C
Yield: 96.1 %

Procedure:
Water (0.5 ml) and potassium carbonate (8.1 mg, 59 μmol) were added to a solution of 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25.0 mg, 45.3 μmol; Example 3) in ethanol (3.4 ml). In a closed pressure-proof glass tube, the reaction mixture was heated at 55° C. For complete conversion, more potassium carbonate was added in two separate portions (5 mg, 36 μmol in total), and the mixture was once more heated at 55° C. 1 N hydrochloric acid (180 μl, 180 μmol) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (24.8 mg, 96% of theory).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([N:21](C(OCC)=O)[CH3:22])[CH2:16]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C>[CH:11]1[C:12]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH3:22])[CH2:16]3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)N(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
The above prepared 1-(9-xanthenyl)-3-(N-carbethoxy-N-methylamino)piperidine (4.5 g.) is refluxed with 100 ml. of a 5M solution of potassium hydroxide in 80 percent aqueous ethanol for three hours. The resulting solution is concentrated in vacuo and the residue poured into cold water. This mixture is extracted with methylene chloride and the organic phase is washed with water and dried over anhydrous potassium carbonate. Evaporation of the solvent gives 1-(9-xanthenyl)-3-methylaminopiperidine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[O:19]>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:15][C:14](=[O:19])[N:13]([CH3:12])[C:17]2=[O:18])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CN1C(=O)CNC1=O
Product: COc1cc(C=C2NC(=O)N(C)C2=O)ccc1O
Yield: 13.4 %

Procedure:
Prepared according to the procedure described in Example 93 using 4-hydroxy-3-methoxybenzaldehyde (3.2 g, 21 mmoles) and 3-methyl hydantoin (3.0 g, 21 mmoles). Recrystallization from ethyl acetate gave the pure product (0.7 g), mp 227°-228° C.
Reaction SMILES: C([C:5]1([NH:31]C(=O)[O-])[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:7][CH2:6]1)(C)(C)C.O1CCOCC1>Cl.C(OCC)C>[NH2:31][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:9][CH:10]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1=CCC(NC(=O)[O-])(C(C)(C)C)C=C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenylcarbamate (Step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl in dioxane (5.74 mL, 22.94 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether (3×30 mL) to afford a tan solid (3.45 g, 69%). 1H NMR (400 MHz, DMF-d6) δ 7.64 (app dt, J=6.58, 8.59 Hz, 1H), 7.31 (ddd, J=2.55, 9.53, 10.61 Hz, 1H) 7.29-7.12 (m, 5H), 6.56 (s, 1H), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 435.0516 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][C@H:22](C(F)(F)F)[CH2:23][N:3]12.NC([C:35]([F:38])([F:37])[F:36])CCCCO.N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O>>[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][CH2:22][C@H:23]([C:35]([F:38])([F:37])[F:36])[N:3]2[C:2]1=[O:1]
Reactant: O=C(N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O)OCc1ccccc1
Reactant: NC(CCCCO)C(F)(F)F
Agent: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Product: N[C@H]1CCS[C@H]2CCC[C@H](C(F)(F)F)N2C1=O

Procedure:
(4S,7R,10aS)-4-Amino-7-(trifluoromethyl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (39 mg, 0.15 mmol) was synthesized as described for the preparation of Intermediate 58 using 5-amino-6,6,6-trifluorohexan-1-ol in step A followed by the preparation of Intermediate 60. Anal. Calcd. for C10H15F3N2OS m/z 268.3. found: 269.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.29 (dd, J=4.4, 2.8 Hz, 1H), 5.13-4.99 (m, 1H), 3.95 (dd, J=10.6, 3.6 Hz, 1H), 3.07 (ddd, J=14.5, 10.0, 3.3 Hz, 1H), 2.74 (ddd, J=14.6, 6.7, 3.3 Hz, 1H), 2.48-2.29 (m, 2H), 2.24 (ddt, J=13.8, 6.9, 3.4 Hz, 1H), 2.16-2.02 (m, 2H), 1.94-1.69 (m, 5H).