Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:10]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Reactant: C1COCCN1
Product: CN1CC(CCN2CCOCC2)Oc2ncccc2C1=S
Reaction time: 6 h

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was dissolved in morpholine (30 ml). The solution was heated with stirring to 50°-60° C. for 6 hr. The morpholine was then removed by rotary evaporation (90° C., vacuum pump). The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2×30 ml). The organic layer was concentrated by rotary evaporation (60° C., water aspirator). The residue was recrystallized from ethanol giving 3.26 g (60%) of light yellow crystals, m.p. 152°-153° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:21]=[CH:20][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1
Reactant: C=Cc1ccncc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccncc4)cc3c21
Temperature: 100 °C
Yield: 65.1 %

Procedure:
Nitrogen was bubbled through a solution of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (3.0 g, 9.4 mmol), 4-vinylpyridine (2.0 mL, 19 mmol), triphenylphosphine (246 mg, 0.94 mmol), and triethylamine (2.7 mL, 19 mmol) in acetonitrile (50 mL) for 15 minutes. Palladium (II) acetate (105 mg, 0.47 mmol) was added, and the reaction was heated at 100° C. for three days. The solvent was removed under reduced pressure, and the residue was adjusted to pH 2 with the addition of concentrated hydrochloric acid. Water was added, and the mixture was filtered through a layer of CELITE filter aid. Aqueous sodium carbonate (2 N) was added to the filtrate to adjust the solution to pH 10. The solution was then extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 2.1 g of 1-(2-methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1.BrC1[C:33]([Cl:39])=[CH:34][C:35]([CH3:38])=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:37]=[N:36][C:35]([CH3:38])=[CH:34][C:33]=2[Cl:39])=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1
Reactant: Cc1cc(Cl)c(Br)cn1
Reactant: COc1ccccc1N(C)S(=O)(=O)c1cc(C2OC(C)(C)C(C)(C)O2)c(Cl)cc1F
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: O
Solvent: C1COCCO1
Product: COc1ccccc1N(C)S(=O)(=O)c1cc(-c2cnc(C)cc2Cl)c(Cl)cc1F
Temperature: 85 °C

Procedure:
4-Chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-benzenesulfonamide (57 mg, 0.125 mmol), 5-bromo-4-chloro-2-methyl-pyridine (21 mg, 0.1 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol), K2CO3 (69 mg, 0.5 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 85° C. for 14 hrs. After the filtration, the mixture was purified by prep. LCMS to afford 4-chloro-5-(4-chloro-6-methyl-pyridin-3-yl)-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzenesulfonamide 3-1. MS: 454.7 (M+H)+; tR=7.77 min (method 2). NMR (CDCl3), δ, 8.350 (1H, s), 7.549 (1H, d, J=6.9 Hz), 7.257-7.436 (5H, m), 6.932 (1H, m), 6.817 (1H, m), 3.513 (3H, s), 3.389 (3H, d, J=2.1 Hz), 2.656 (3H, s).
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:35][CH2:36][CH:37]4[CH2:39][CH2:38]4)=[N:13][N:14]([CH3:34])[C:15]=3[NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:33])([CH3:32])[C:27]([O:29]CC)=[O:28])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1>CO.O.O1CCCC1>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:35][CH2:36][CH:37]4[CH2:39][CH2:38]4)=[N:13][N:14]([CH3:34])[C:15]=3[NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:33])([CH3:32])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=3)(=[O:18])=[O:19])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCC3CC3)nn2C)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(OCC2CC2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C(=O)O)cc1
Yield: 36.6 %

Procedure:
An aqueous solution of sodium hydroxyde (2N, 1 ml) was slowly added to a solution of ethyl 2-{4-[([4-(1,3-benzodioxol-5-yl)-3-(cyclopropylmethoxy)-1-methyl-1H-pyrazol-5-yl]amino)sulfonyl]phenyl}-2-methylpropanoate (Example 75) (83 mg) in a mixture of methanol:water:tetrahydrofuran (1:1:1) (6 ml) and the reaction was heated to 50C for 24 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (8 ml) and extracted with dichloromethane (3×8 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC eluted with dichloromethane:methanol (9:1) yielding the title compound as a white solid (28.8 mg).
Reaction SMILES: C[O:2][C:3](=[O:50])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](=[O:33])[CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]([C:41](=[O:43])[CH3:42])[CH:29]2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>CCO.CC(O)=O>[C:41]([N:30]1[CH:31]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:32](=[O:33])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:50])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:7])=[CH:23][CH:24]=2)[CH:29]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)(=[O:43])[CH3:42]
Reactant: COC(=O)[C@H](Cc1ccc(N2C(=O)C(Cc3ccccc3)N(C(C)=O)C2c2ccccc2)cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1C(Cc2ccccc2)C(=O)N(c2ccc(C[C@H](NC(=O)C3(CCCCS(C)(=O)=O)CCCC3)C(=O)O)cc2)C1c1ccccc1
Yield: 95 %

Procedure:
4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester diastereomer 1 (90 mg, 0.128 mmol) in EtOH (3 mL) was treated with NaOH (1N, 0.3 mL) at room temperature for 30 min. The resulting solution was acidified with 1 drop of HOAc and was purified by HPLC (C-18, linear gradent from 5% acetonitrile to 95% in water over 30 min) to give 84 mg (95%, 0.122 mmol) of 4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine diastereomer 1. LR MS: 688 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[O:21]1CCOCC1>>[Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(Br)c(O[Si](C)(C)C(C)(C)C)c2n1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=O)nc12
Temperature: 80 °C
Reaction time: 32 h
Yield: 89 %

Procedure:
A slurry of SeO2 (0.869 g, 7.83 mmol) and 1,4-dioxane (20 mL) was warmed to 80° C. and the product from Step B (2.3 g, 6.53 mmol) was added as a 1,4-dioxane solution (20 mL). The mixture was stirred at 80° C. for 32 hours and then cooled to ambient temperature and filtered through GF/F filter paper. The residual solid was washed with CH2Cl2, and the filtrate was concentrated and purified by passing through a silica gel plug, eluting with 50% CH2Cl2/hex to provide 2.14 g (89%) of the product as a yellow/orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.Cl[CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>CN(C)C=O.O>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:32]=3)[CH:9]=2)[CH:12]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCOCC3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (199 mg, 0.468 mmol) in N,N-dimethylformamide (5 mL) was added chloroacetyl chloride (76 μL, 0.842 mmol), and the mixture was stirred at room temperature for 1 hr. Water (15 mL) was added to the reaction mixture, and extracted with ethyl acetate (20 mL, 2×5 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and fractions containing the desired product were concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). Triethylamine (195 μL, 1.40 mmol) and morpholine (122 μL, 1.40 mmol) were added, and the mixture was stirred at 60° C. for 3 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 2×5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→99/1), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration and dried over to give the title compound (144 mg, 56%) as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=3)[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)cs2)cc(C(C)(C)C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nc(CCOc3ccc(C=O)cc3)cs2)cc(C(C)(C)C)c1O
Temperature: -10 °C
Yield: 72.2 %

Procedure:
The compound of Step E 4.20 g (12.6 mmole), 1.76 g (14.44 mmole) 4-hydroxybenzaldehyde, and 3.79 g (14.44 mmole) triphenyl phosphine were dissolved in 37 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to -10° C. and a solution of 2.27 ml (14.44 mmole) diethylazodicarboxylate in 12.5 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to -1° C. The bath was removed and the reaction stirred under nitrogen overnight. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 15 then 20% ethyl acetate/hexane. The appropriate fractions were bulked and stripped to give 3.98 g (72%) product which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[N:24]=[N:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[OH:36]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:23]2[N:24]=[N:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[O:36][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Oc5ccccc5)nn4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.79 mmol), 2-fluoro-4-(6-phenoxy-pyridazin-3-yl)-phenol (Step 2, 0.50 g, 1.79 mmol) and DMAP (0.22 g, 1.79 mmol) in 6 mL of toluene (in microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1 h.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N

Procedure:
A 40.8 g portion of 5-nitro-anthranilonitrile and 40 mL of N,N-dimethylformamide dimethyl acetal were heated on a steam bath for 2 hours. The solvents were removed at reduced pressure and the residue was taken up in methylene chloride. After passing this solution through Magnesol the solvent was removed. After washing with ether 50.8 g of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9]\[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1
Solvent: O
Product: Cc1ccc(C(=CCN2CCCC2)c2ccccn2)cc1
Reaction time: 3 h
Yield: 52.4 %

Procedure:
60 ml of demineralized water is charged into a round-bottomed flask kept at 25° to 30° C. and then slowly 540 ml of 90% Conc. H2SO4 is added and the temperature is raised to 40° C.-60° C. under stirring. Slowly 200 g of 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol is charged and the temperature is maintained at 85° C. under stirring. The reaction mass is heated to 100-105° C. and the temperature is maintained for 4 hours under stirring. After completion of the reaction, the reaction mass is cooled to 25°-30° C. and then poured into ice cold water (4 litre) at 5-10° C. under stirring over a period of an hour. 50% NaOH solution (w/w) is added slowly to the reaction mixture by maintaining the temperature at 5° to 20° C. over a period of 2 hours and the contents are stirred for an hour at 25° to 30° C. The reaction mixture is filtered under suction to obtain 286 g of wet triprolidine base comprising >92% E-isomer along with <8% Z-isomer. 2 litres of demineralized water and 286 g of wet triprolidine base are charged into a round-bottom flask at 25° to 30° C. and the contents are stirred for 3 hours by maintaining the same temperature. The contents are filtered and dried under suction for 2 hours. The process is repeated thrice to obtain 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidino prop-1-ene (150 g, 80%) consisting of >98% E isomer along with <2% Z-isomer.
Reaction SMILES: [C:1](=[O:9])([O:7][CH3:8])[O:2][CH2:3][CH:4]([F:6])[F:5].[C:10](Cl)(=O)OCC.C(Cl)(=O)OC>>[C:1](=[O:9])([O:7][CH2:8][CH3:10])[O:2][CH2:3][CH:4]([F:6])[F:5]
Reactant: COC(=O)OCC(F)F
Reactant: CCOC(=O)Cl
Agent: COC(=O)Cl
Product: CCOC(=O)OCC(F)F

Procedure:
2,2-Difluoroethyl ethyl carbonate was prepared as in [Synthesis of 2,2-Difluoroethyl Methyl Carbonate] of Example IV-1, except that ethyl chlorocarbonate (7.9 g, 0.073 mol) was substituted for methyl chlorocarbonate (6.9 g, 0.073 mol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:17][OH:18])[CH:6]=[CH:5]2.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:17][O:18][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CN(C)c1c(Br)cc2ccc(CO)nc2c1C#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C)c1c(Br)cc2ccc(CO[Si](C)(C)C(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
The 6-bromo-7-dimethylamino-2-(hydroxymethyl)quinoline-8-carbonitrile (2 g, 6.5 mmol, 1 eq), TBDMSCl (1.4 g, 7.3 mmol, 1.1 eq) and imidazole (623 mg, 7.3 mmol, 1.1 eq) were added to DMF (20 mL). The resulting solution was stirred at room temperature for 3 hours, and then the solvent was removed under high reduced pressure. Cyclohexane was added and the mixture was washed twice with water, and then with brine. The organic layer was then dried over MgSO4, and concentrated under reduced pressure. The product was obtained pure as a yellow powder (1.9 g, 68%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:31][CH:30]=3)[S:28][C:19]=12
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCOCC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Morpholine (16 mg, 0.18 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (66 mg, 0.15 mmol) in 5 mL of dichloromethane and 0.5 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (85 mg, 0.40 mmol) is added. After stirring at 0° C. for 1.5 hours, acetic acid (0.02 mL) is added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography to provide 48 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 244-245° C.; 1H NMR (DMSO-d6) δ 2.36 (m, 4H), 3.50 (s, 2H), 3.57 (m, 4H), 3.85 (s, 3H), 7.31 (s, 1H), 7.42 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 525.2 (M+H)+.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]#[N:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:25][N:24]=[N:23][N:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(C#N)cc1COc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2nnn[nH]2)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (100 mg, 0.35 mmoles), sodium azide (27 mg, 0.415 mmoles) and potassium carbonate (62 mg, 0.45 mmoles) in dimethylformamide (5 ml) was heated at 90° C. for 96 hours then at 120° C. for 24 hours. The mixture was evaporated and the residue purified by HPLC to afford compound 149 as a white solid (64 mg). LC/MS System D; Rt=9.53 mins, m/z (ES+)=333 (M+H for C19H16N4O2).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@H:28]2[O:32][C:31](=[O:33])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:31](=[O:33])[CH2:30][CH2:29][C@H:28]([OH:32])[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H]2CCC(=O)O2)c1
Reactant: Nc1cnc(Oc2ccc(Cl)cc2)cn1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc([C@@H](O)CCC(=O)Nc2cnc(Oc3ccc(Cl)cc3)cn2)c1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenoxy)pyrazin-2-amine (149 mg, 0.67 mmol) in dry CH2Cl2 (1.5 mL) at room temperature, under argon, is added trimethylaluminum (0.335 mL of a 2.0 N solution in toluene, 0.67 mmol) dropwise. The resulting mixture is stirred for 15 min, then (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one (107 mg, 0.555 mmol) in CH2Cl2 (1.5 mL) is added slowly and stirring is continued at ambient temperature for 3 days. The reaction is quenched carefully with 10% aqueous citric acid (0.5 mL) at 0° C. The mixture is then partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL). The aqueous layer is extracted further with CH2Cl2 (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified on silica gel (0-75% ethyl acetate in hexane) to give (S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl)butanamide (230 mg, 100%) as a white solid.