Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][O:19][CH2:20][C:21](OC)=[O:22])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.CO.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:21](=[O:22])[CH2:20][O:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:25])([F:26])[F:1])=[N:4][N:5]=3)[N:8]=2)[CH2:17][CH2:16]1
Reactant: CNC
Reactant: COC(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: CO
Product: CN(C)C(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 48.8 %

Procedure:
A stirred solution of methyl 2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetate (95 mg, 0.25 mmol) in 2M dimethylamine in methanol (2.0 mL, 4.00 mmol) was heated at 120° C. in a microwave reactor for 1 hour. The reaction mixture was evaporated and the crude product was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N,N-dimethyl-2-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetamide (48.0 mg, 48.8%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2].[Cl:13][CH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:13][CH2:14][CH2:15][C@@H:16]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:3]([CH2:1][CH3:2])[C:4]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCn1c(=O)[nH]c2ccccc21
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1c(=O)n([C@H](CCCl)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To a mixture of 1-ethyl-1,3-dihydro-benzimidazol-2-one (1 g, 6.2 mmol), (S)-(−)-3-chloro-1-phenyl-1-propanol (1.16 g, 6.8 mmol), and triphenylphosphine (1.78 g, 6.8 mmol) in anhydrous THF (25 mL) was added DIAD (1.38 g, 6.8 mmol) under nitrogen at room temperature. The mixture was stirred under nitrogen at room temperature for 18 hrs and solvent removed in vacuo. The residue was purified by a silica gel column (33% ethyl acetate in hexane) to afford 1-[(1R)-3-chloro-1-phenylpropyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one as an oil (0.5g, 26%). MS (ESI) m/z 315.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)(Cl)(Cl)Cl.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:26])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Four point five grams of 3-chloro-4-hydroxybenzoic acid were dispersed in a mixed solvent of 30 ml of carbon tetrachloride and 5 ml of pyridine and then heated. 3.7 g of nonanic acid chloride was dropped into the mixture with refluxing. After heating 3 hours the solvent was removed from the mixture. After decomposing unreacted nonanic acid chloride by adding a small amount of water, the residue was washed with methanol to obtain 3-chloro-4-octylcarbonyloxybenzoic acid (AE). After dispersing the compound (AE) into 20 ml of carbon tetrachloride, (AE) was reacted with 5 ml of thionyl chloride with refluxing for 3 hours. 6.5 g of 3-chloro-4-octylcarbonyloxybenzoic acid chloride (AF) was obtained after removing solvent.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH:5]([C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[O:4][CH2:3][CH2:2]2.CO.[Cl-].[NH4+].[N-:22]=[N+:23]=[N-:24].[Na+]>O>[N:22]([CH:1]1[CH2:2][CH2:3][O:4][CH:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH:7]1[OH:8])=[N+:23]=[N-:24]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC2OC2CCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1C1CC(O)C(N=[N+]=[N-])CCO1
Temperature: 70 °C
Yield: 58.5 %

Procedure:
To a solution of 5-(4,8-dioxabicyclo[5.1.0]octan-5-yl)-1-methyl-4-nitro-pyrazole (1.04 g, 4.35 mmol) in 4:1 MeOH:water (30 mL) was added ammonium chloride (0.58 g, 10.88 mmol) and sodium azide (1.41 g, 21.75 mmol). The mixture was heated at 70° C. behind a blast screen for 16 hr. The MeOH was removed under reduced pressure and EtOAc (20 mL) added. The organic layer was washed with saturated aqueous NaHCO3 (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-60% EtOAc/isohexane) gave 5-azido-2-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a pale yellow gum (718 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.76 (dd, J=9.3, 3.2 Hz, 1H), 4.18-4.10 (m, 1H), 4.08-4.04 (m, 4H), 3.91 (ddd, J=9.4, 6.6, 6.2 Hz, 1H), 3.79 (ddd, J=12.6, 8.6, 3.5 Hz, 1H), 2.44 (ddd, J=15.3, 9.4, 3.8 Hz, 1H), 2.37-2.29 (m, 1H), 2.24 (d, J=3.2 Hz, 1H), 2.12 (ddd, J=15.3, 5.7, 3.2 Hz, 1H), 2.06-1.96 (m, 1H).
Reaction SMILES: [OH:1]O.[CH2:3]([NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1)[CH3:4]>CC(O)=O.C([O-])(O)=O.[Na+]>[CH2:3]([NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N+:11]=1[O-:1])[CH3:4]
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Reactant: OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CO)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
H2O2 (70%, 1.0 mL, ca. 20.0 mmol) was added dropwise to a stirred solution of 1-oxide 126 (71 mg, 0.27 mmol) in HOAc (3 mL) at 50° C. and the reaction was stirred at 50° C. for 20 h. The mixture was diluted with aqueous NaHCO3 solution and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1,4-dioxide 127 (11 mg, 15%) as a red solid: mp (MeOH/DCM) 153-155° C.; 1H NMR δ 8.10 (s, 1H, H-9), 8.05 (s, 1H, H-5), 7.01 (br s, 1H, NH), 3.69 (d, J=6.5 Hz, 2H, CH2O), 3.59-3.67 (m, 2H, CH2N), 3.15-3.28 (m, 2H, CH2), 2.90-3.03 (m, 2H, CH2), 2.72-2.86 (m, 1H, CH), 1.35 (t, J=7.2 Hz, 3H, CH3), OH not observed; HRMS calcd for C13H16N4O3 (M+) m/z 276.1222, found 276.1222.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]3)[N:6]=[CH:5]2.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]6)=[CH:35][CH:34]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Nc1ccc2c(cnn2-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc2c(cnn2-c2ccc3[nH]ccc3c2)c1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 1043 was prepared according to the procedure described in Scheme IV from 5-amino-1-(indol-5-yl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoic acid.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>ClCCCl.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]=[C:14]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH:15]([OH:20])[C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1Cl)n1cncn1
Yield: 63.8 %

Procedure:
166 Milligrams (1.02 mmole) of the present compound obtained in Example 1 was dissolved in a 1,2-dichloroethane/dimethylformamide (27 ml/0.5 ml) mixed solvent, and 5 ml of a 1,2-dichloroethane solution containing 975 mg (3.0 mmoles) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=94.8/5.2) was added dropwise thereto. After reaction at room temperature for 16.5 hours, 2% hydrochloric acid was added to separate the reaction solution into an aqueous and organic layers. After concentrating the organic layer, the residue was purified by column chromatography on silica gel to obtain 624 mg of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The ratio of the E-form alcohol to Z-form alcohol was 93.8 to 6.2, and the enantiomer ratio of the E-form alcohol was: (+)-isomer: (-)-isomer=18:82.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:12]=3)[CH2:7]2)[C:5](=[O:27])[NH:4][C:3]1=[O:28].Cl.N>CCOC(C)=O.CO>[NH2:18][CH2:17][C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@:6]1([C:5](=[O:27])[NH:4][C:3](=[O:28])[N:2]1[CH3:1])[CH2:14]2)=[O:26]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1C2
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN)cc1C2
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl (2-{[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]amino}-2-oxoethyl)carbamate from Step A (1.80 g, 4.63 mmol) in EtOAc (50 mL), at 0° C., was added anhydrous HCl (bubbled in through a pipet, for 5 minutes). After an additional 30 minutes of standing at 0° C., the solvent and excess HCl was removed in vacuo to yield a solid. This solid was then dissolved in the minimal amount of MeOH and treated with a methanolic 2 N ammonia solution (20 mL, 40 mmol). This mixture was stirred for 30 min at ambient temperature, before the bulk of the MeOH was removed in vacuo. The residue was applied to a silica gel column for purification, eluting with DCM:MeOH (10% conc. NH4OH)—95:5 to 85:15. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1.CS[C:20](SC)=[CH:21][N+:22]([O-:24])=[O:23]>>[N+:22]([CH:21]=[C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccc(CNCC(F)(F)F)o1
Product: O=[N+]([O-])C=C(NCCSCc1ccc(CNCC(F)(F)F)o1)NCCSCc1ccc(CNCC(F)(F)F)o1
Yield: 21.8 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]-N-(2,2,2-trifluoroethyl)-2-furanmethanamine (0.83 g) and 1,1-bis-(methylthio)-2-nitroethene (0.25 g) was heated at 98°-100° for 3 hr. The gummy residue was chromatographed (silica/ethyl acetate then ethyl acetate/ethanol 9:1) and the appropriate eluate evaporated to dryness to give the title compound (0.2 g) as an oil.
Reaction SMILES: F[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CS(C)=O>[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][N:36]([C:2]3[C:11]([O:12][CH3:13])=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:4][CH:3]=3)[CH2:35]2)[CH2:31][CH2:32][CH2:33]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CCC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CCC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 112 h

Procedure:
A mixture of 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (290 mg, 0.98 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidine (283 mg, 1.18 mmol), triethylamine (0.409 ml, 2.94 mmol), and dimethyl sulfoxide (5 ml) was stirred for 112 hours while heating in an oil bath at 80° C. under an argon-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the organic layer was washed with saturated saline solution (30 ml). The organic layer obtained was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was subject to a silica gel chromatography and a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was thereby obtained from a chloroform:methanol=20:1 eluate.
Reaction SMILES: [CH:1]([C:3]1[C:7](Br)=[CH:6][S:5][CH:4]=1)=[O:2].[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:7]2[C:3]([CH:1]=[O:2])=[CH:4][S:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(OCOC)cc1
Reactant: O=Cc1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#Cc2cscc2C=O)cc1
Yield: 66.9 %

Procedure:
3-Formyl-4-bromothiophene (14.7 g) was dissolved in DMF (100 ml), followed by the addition of triethylamine (100 ml) CuI (0.25 g), Pd(PPh3)2Cl2 (0.5 g) and 4-methoxymethoxy-1-ethynylbenzene (11.4 g), and the mixture was reacted at 70° C. overnight. The reaction solution was filtered through Celite, poured into 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and brine, dried and evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give 3-{[4-(methoxymethoxy)phenyl]ethynyl}-4-formylthiophene as a colorless oil (12.8 g, yield; 47%).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=O)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5]>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH2:9][C:10]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CN(CC(=O)NCc1nccs1)C(=O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CN(Cc1ncc2sccn12)C(=O)C(F)(F)F
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
To 3.02 g (10.3 mmol) of the above-obtained 2-(N-methyl-N-trifluoroacetylaminomethylcarbonyl)aminomethylthiazole was added 40 ml of phosphorus oxychloride, and the mixture was stirred at 10° C. for 1.5 hours and then at 120° C. for 5 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the residue were added a small amount of ice and 15 ml of a 50% aqueous solution of potassium carbonate. The mixture was stirred, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 1:9 mixture of hexane and ethyl acetate to give 490 mg (yield 18%) of 5-(N-methyl-N-trifluoroacetylamino)methylimidazo[5,1-b]thiazole as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(c1ccccc1)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
3-Nitro-4-chloro-benzophenone is reacted with morpholine as described in Example 7 to obtain 3-nitro-4-morpholino-benzophenone with a yield of 98% (compound B2, supra. The product melts at 103°C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:5].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>ClCCl.CN(C)C=O>[CH2:11]([C@H:3]([NH:2][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[C:4]([N:6]1[CH2:7][CH:8]([OH:10])[CH2:9]1)=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(Cc1ccccc1)C(=O)N1CC(O)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Cl)ccc2[nH]1
Yield: 38.3 %

Procedure:
2-Amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride (1.18 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.18 mmol) were coupled according to Procedure A (4:1 dichloromethane-dimethylformamide reaction solvent) and the product purified by chromatography on silica gel eluted with 25%, 50%, 75% and 100% ethyl acetate-hexanes giving the title substance as a colorless foam (104 mg, 22%). A mixture (180 mg) of less polar products was also isolated. Title substance:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH3:35])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:39]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH2:35][CH:2]([CH3:3])[CH3:39])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)cs4)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(C)C)cs4)cc23)CC1
Yield: 25 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (0.1 mL) for 2 M methylamine to afford 15.4 mg of the title compound (25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:26](=[O:28])[CH3:27])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(4-piperidyloxy)benzoic acid (0.6 g, 2.09 mmol) was stirred in THF (10 ml) and treated with triethylamine (0.29 ml, 0.21 g, 2.08 mmol), followed by acetyl chloride (0.18 ml, 0.2 g, 2.5 mmol) and an additional 0.35 ml of triethylamine. The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer was extracted with sodium bicarbonate solution. The combined sodium bicarbonate layers were acidified with 1N HCl and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: Clc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Clc1cccc2c1ccn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 16.9 g of 4-chloro-1H-indole, 170 ml of benzene, 85 ml of aqueous 50% sodium hydroxide solution, 1.89 g of n-tetrabutyl ammonium hydrogen sulfate and 16.6 ml of benzyl chloride was heated at 60° C. with strong stirring for 4 hours and was then cooled to room temperature. The decanted organic phase was washed with water, dried and evaporated to dryness. The 30.2 g of residue were chromatographed over silica gel and were eluted with cyclohexane to obtain 22.8 g of 4-chloro-1-benzyl-1H-indole melting at 58°-60° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:10]2[C:17]([CH3:18])=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[Br:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[N:35][C:36]#[N:37])OC2C=CC=CC=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:26]/[C:27](/[N:6]2[CH2:7][CH:2]([CH3:1])[N:3]([C:9]3[C:10]4[C:17]([CH3:18])=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:4][CH:5]2[CH3:8])=[N:35]\[C:36]#[N:37])[CH:23]=[CH:24][CH:25]=1
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3C[C@@H](C)NC[C@@H]3C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CC(C)N(/C(=N/C#N)Nc4cccc(Br)c4)CC3C)c12
Temperature: 150 °C
Yield: 19 %

Procedure:
The dimethyl piperazine from step A (80 mg, 0.32 mmol), phenyl N-3-bromophenyl-N′-cyanocarbamimidate, from Example 5, step A, (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.20 ml) were added to isopropanol (10 ml). The mixture was heated at 150° C. for 20 min in a microwave, then concentrated under vacuum. The material was purified prep HPLC (Sunfire C18 30×250 mm column, 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min) to give (E)-N-(3-bromophenyl)-N′-cyano-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (29 mg, 0.062 mmol, 19%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](OC)=[O:26].O>ClCCl>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: COC(=O)CCCCC=Cc1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: OCCCCCC=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Di-isobutylaluminium hydride (1.0M in dichloromethane, 308 ml, 308 mmol) was injected into a stirred solution of methyl 7-(2,4-dichlorophenyl)-6-heptenoate (40.2 g, 140 mmol) in dichloromethane (200 ml) at -78° C. under argon. After 5 min, the solution was warmed to 0° C., stirred for 0.5 h, then cooled again to -78° C. Water (102 ml) was injected slowly, while allowing the mixture to warm to room temperature. When solid had precipitated, ethyl acetate (400 ml) was added, then excess NaHCO3, and the mixture stirred vigorously for 0.25 h. The solids were filtered off, the solvent removed under vacuum, and the residue purified by chromatography on silica gel (30-70% ether/petroleum ether 40°-60° C.) to give the title compound (31.7 g, 85%) as an oil, comprising a mixture of E and Z isomers.