Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(CO)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 51.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) were added HBTU (0.185 g, 0.49 mmol) and Et3N (205 μL, 1.47 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 minutes before a slurry of 2-(5-amino-1H-indol-2-yl)propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was stirred at room temperature for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=13/7) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.095 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s, 1H), 6.02 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 3.68-3.63 (m, 1H), 3.50-3.44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1.26 (d, J=7.0 Hz, 3H), 1.05-1.02 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([OH:18])=O)(=[O:10])=[O:9])[CH:2]=1.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[S:8](=[O:9])(=[O:10])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)Nc1cccnc1
Reactant: NCCCc1ccccc1
Product: O=C(NCCCc1ccccc1)[C@@H]1CCCN1S(=O)(=O)Nc1cccnc1

Procedure:
Compound 118 was prepared from the carboxylic acid (compound 116) and 3-phenyl-propylamine by a synthetic method analogous to the step 2 of compound 31 synthesis. A 21% yield was obtained for the title compound.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+].C(O)C>O.Cl>[C:20]1([NH:26][N:27]=[C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]([NH2:15])=[O:14])[C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=NNc2ccccc2)c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 0.2 g (0.8 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, 0.5 g (4.6 mmol) of phenylhydrazine and 0.5 g (6 mmol) of sodium acetate in a mixture of 5 mL of water, 5 mL of ethanol and 3 drops of concentrated hydrochloric acid was heated at 60° C. for thirty minutes and then allowed to cool to room temperature. The precipitate was then filtered and washed with cold water and dilute ethanol to give the desired product as yellow crystals of m.p. 220° to 220.8° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:29][C:30]1[C:38]([I:39])=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=1)[N:6]2[CH2:11][C@@H:12]([C:21]([O:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])[NH:13]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:29][C:30]1[C:38]([I:39])=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=1)[N:6]2[CH2:11][C@@H:12]([C:21]([O:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:22])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21)C(=O)OC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2C[C@H](N)C(=O)OC1CCCC1
Yield: 78.2 %

Procedure:
A solution of cyclopentyl 3-{6-amino-8-[(6-iodo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}-N-(tert-butoxycarbonyl)-L-alaninate (21 mg, 0.027 mmol) in TFA (250 μl, 3.24 mmol) and DCM (1 ml) was stirred at room temp for 2 h. LC-MS analysis showed complete formation of the product. The solvent was evaporated and the residue purified on SCX (0.5 g) to afford the title compound (12 mg) as a pale yellow solid. m/z 569 [M+H]+. 1H NMR (400 MHz, CHCl3-d) d: 8.31 (1H, s), 7.23 (1H, s), 6.93 (1H, s), 5.97 (2H, s), 5.61 (2H, br. s), 5.13 (1H, m), 4.50 (1H, dd, J=14.2, 5.9 Hz), 4.33 (1H, dd, J=113.9, 8.6 Hz), 3.98 (1H, dd, J=8.8, 5.9 Hz), 1.8-1.54 (10H, br m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>CCCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC#Cc1ccc(C#N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and 1-octyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (100 mg, 95%); 1H NMR δ (CDCl3): 7.56 (d, J=8.61 Hz, 2H), 7.46 (d, J=8.62 Hz, 2H), 2.43 (t, J=7.44 Hz, 2H), 1.6 (p, J=7.37 Hz, 2H), 1.5-1.4 (m, 2H), 1.38-1.26 (m, 4H), 0.92 (t, J=7.36 Hz, 3H); LCMS m/z: 211.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.N1C=CC=CC=1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([CH3:31])=[CH:23][CH:24]=3)=[O:30])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(6-Chloro-pyrimidin-4-yloxy)-phenylamine (331 mg, 1.50 mmol) is dissolved in DMF (3 mL) under an argon atmosphere at rt. Pyridine (133.2 μL, 1.65 mmol) is added dropwise followed by dropwise addition of p-tolylisocyanate (221 μL, 1.80 mmol). The reaction Is stirred for 30 min at rt. The solvent is removed in vacuo and the residual crude product is titurated with ethyl acetate/hexanes 9:1 to give the title compound as a white powder: m.p.=217-219° C.; C18H15N4O2Cl: M+=355.1; 1H-NMR (DMSO-d6): 8.78 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H, HN), 7.52 (d, 2H), 7.37 (d, 2H), 7.17 (d, 2H), 7.05 (d, 2H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[S:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[N:26]=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:31]3[CH:30]=[CH:29][C:28]4[S:24][N:25]=[N:26][C:27]=4[CH:32]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1ccc2snnc2c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4snnc4c3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with benzo[1,2,3]thiadiazole-5-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=495.0.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@H:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[CH3:30][C:31]1([C:34](Cl)=O)[CH2:33][CH2:32]1>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][C@@H:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:30]([C:31]6([CH3:34])[CH2:33][CH2:32]6)[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(C(=N)NO)CC2)C3)CC1
Reactant: CC1(C(=O)Cl)CC1
Product: CC1(c2nc(N3CCC([C@@H]4Cc5cc(C6=CCN(S(C)(=O)=O)CC6)ncc5O4)CC3)no2)CC1

Procedure:
The title compound is prepared from (S)—N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (Intermediate 47; the configuration of the stereocenter is arbitrarily assigned) and 1-methyl-cyclopropanecarbonyl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.53 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:11]1(=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[C:25]([C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:24]=2)[CH2:29]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccccc1)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
0.70 g of phenylacetic acid chloride dissolved in 5 ml of dichloroethane was added under ice cooling to 1.00 g of 2-(1,3-isoindolinedion-2-yl)indane and 1.27 g of anhydrous aluminum chloride suspended in 15 ml of dichloroethane, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for l hour. The reaction mixture was poured into ice water and extracted with chloroform. After the organic layer was washed with water and dried, the solvent was removed. The resulting crystals were recrystallized from ethyl acetate to obtain 1.05 g of 2-(1,3-isoindolinedion-2-yl)-5-(2-phenylacetyl)indane.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH3:22])=[C:15]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:23]([C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:11][CH:10]=3)[CH:13]=2)[N:17]([CH3:21])[C:16]=1[CH3:22])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC(=O)O)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.151 g, 0.378 mmol) was reacted with 1N KOH (0.8 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.068 g, 0.176 mmol, 47%) as a yellow solid, mp 204-207° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.67 (s, 3H), 4.06 (s, 2H), 4.67 (s, 2H), 6.94 (d, J=8.9 Hz, 2H), 7.08-7.12 (m, 1H), 7.19-7.24 (m, 4H), 7.28 (dd, J=1.7, 8.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 2H), 7.56 (d, J=1.4 Hz, 1H); IR (solid) 3020, 2880, 1740, 1710, 1510, 1480, and 1230 cm−1; [ESI(+)], m/z 386 (M+H)+; Anal. Calcd. for C25H23NO3.0.3H2O: C, 76.82; H, 6.17; N, 3.58; Found: C, 76.66; H, 6.00; N, 3.46.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([O:26]C(OCC)C)[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:26])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
iv)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (66.1 g) in acetone (1330 ml) was treated with a 4 M aqueous solution of hydrochloric acid (13.2 ml). The reaction mixture was stirred for 45 min. and subsequently poured into a mixture of water (3 l) and a saturated aqueous solution of sodium hydrogen carbonate (500 ml). The resulting precipitate was collected by filtration and then dissolved in dichloromethane. The filtrate was extracted with ethyl acetate. The dichloromethane and ethyl acetate solutions were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-pregn-5-ene-3,20-diol 20-acetate (compound 5; 53.5 g), which was used in the following step without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)([CH3:5])[CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=1>CN(C=O)C>[CH3:31][S:30][C:26]1[N:27]=[C:28]([N:12]2[C:13]3[C:9](=[C:8]([O:7][Si:6]([CH:3]([CH3:5])[CH3:4])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)[CH:29]=[CH:24][N:25]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccc3c(O[Si](C(C)C)(C(C)C)C(C)C)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (1.826 g) was added to DMF (400 mL) and cooled to 0° C. 4-(Triisopropyl-silyloxy)-1H-indole (12 g) was added portionwise at 0° C., and allowed to stir at 0° C. for 1 h. 4-Chloro-2-methylsulfanyl-pyrimidine (5.28 mL) was added dropwise, and the reaction mixture stirred at 0° C. for 4 h and then quenched with water. The aqueous layer was acidified with 1N HCl. The organic layer was extracted into DCM, and dried over sodium sulfate, filtered and the filtrate was concentrated and purified on a column with 100% hexane to 25% EtOAc/hexane to yield 1-(2-methylsulfanyl-pyrimidin-4-yl)-4-triisopropylsilanyloxy-1H-indole (11 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][C:41]([CH3:43])=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[O:27]1[C:31]2([CH2:32][CH2:33][CH:34]([N:37]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:39]4[N:40]=[C:41]([CH3:43])[N:42]=[C:38]34)[CH2:35][CH2:36]2)[O:30][CH2:29][CH2:28]1
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 200 °C
Reaction time: 48 h
Yield: 36.4 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (44 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (15 g) and N,N-diethylaniline (100 mL) was stirred at 200° C. for 48 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (12 g, 36%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:49][NH2:50]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][NH:50][CH3:49])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.476 g, 0.777 mmol) in 2.0 M methylamine in THF (8.0 mL, 16 mmol) was stirred at 70° C. in a sealed tube for 3 hours. After cooling to ambient temperature and concentrating, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-methyl-amine as a clear, dark yellow gum (0.324 g, 88.5%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 81° C. in vacuo for 13 hours. The hydrochloride as a light orange foam (0.330 g) resulted; Mass Spectrum (+EI, [M+H]+) m/z 472. 1HNMR (500 MHz, DMSO-d6): δ8.86 (s, 2H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.27 (d, 1H, J=3.30 Hz), 7.09-7.18 (m, 6H), 5.70 (s, 2H), 4.24-4.27 (m, 2H), 2.59 ppm (s, 3H). Elemental Analysis for C27H25N3O3S2.1.00 HCl.0.55 mol H2O: Calcd: C, 62.61; H, 5.27; N, 8.11; Found: C, 62.23; H, 5.45; N, 7.72.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:22]=[C:21]([Br:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:24][CH3:25].CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>C1COCC1>[Br:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:24][CH3:25])=[C:13]([CH:28]=[O:29])[CH:22]=1
Reactant: CN(C)C=O
Reactant: COc1c(Br)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C=O)cc(Br)c2ccccc12
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 56.9 ml, 91.1 mmol) was added dropwise to a solution of 2,4-dibromo-1-methoxy-naphthalene (30.3 g, 95.9 mmol) in THF (1,800 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this mixture, N,N-dimethylformamide (8.9 ml, 115.1 mmol) was added at −78° C. The mixture was stirred at the same temperature for three hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:8)] to obtain the title compound (3.85 g, 15%).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][NH:28][CH2:27]2)[CH3:25])=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([CH3:25])[CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:29][N:28]([C:7]([Cl:10])=[O:6])[CH2:27]2)=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)C1CN(C(=O)Cl)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.1 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (12 mg, 0.040 mmol) in CH2Cl2 (3 ml) at −78° C., was added a solution of rac-2-(3,5-dichloro-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (Intermediate VII-5), (41 mg, 0.10 mmol) and pyridine (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 37 mg (79%) of the title compound as_colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[NH2:30]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:25][N:30]=[C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 40.5 mg (0.295 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 28.8 mg (21% of theory).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(=O)(O)[O-].[Na+].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2.Cl>C(Cl)Cl>[CH3:16][N:17]([C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:9])[CH2:18][CH2:19][CH2:20][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2
Reactant: O=C(Cl)c1cccnc1
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)c1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was suspended in methylene chloride (12 ml) cooled to 5° C. and sodium bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred for 3 hours at 5° C. The sodium chloride was removed by filtration and the organic solution was extracted with aqueous sodium bicarbonate, dried over sodium sulfate, filtered through Celite™ and concentrated. Ethyl ether (5 ml) was added to the oily residue and white crystals formed. Yield 62% (0.58 g), m.p. 84°-86° C. The product has the formula: ##STR1616##