Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[C:14]1[C:15]2[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:2][CH3:3].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C@@H:35]([NH:38][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:6]4[C:7]5[O:11][CH2:10][O:9][C:8]=5[CH:12]=[CH:13][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A70) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C[CH:2]([C:9]1[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([O:19][CH2:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=1)=[CH:13][CH:12]=2)[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C1COCC1.[Li+].[OH-].Cl>CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:13][CH:12]=3)[C:17]([CH3:18])=[C:9]2[CH2:2][C:3]([CH3:7])([CH3:8])[C:4]([OH:6])=[O:5])=[CH:33][CH:34]=1
Reactant: Cc1c(C(C)C(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4c3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4c3)cc12

Procedure:
A solution of the ester from Step 1 (278 mg), 3 mL THF, 3 mL MeOH, and 2.7 mL 1N LiOH was stirred at 80° C. for 4 hours under nitrogen. The solution was cooled, poured onto 1N HCl, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated. Purification of the residue by chromatography (silica gel; hexane/EtOAc 2:1) gave the title compound as a solid, m.p. 151.5°-152.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:10][C:11]([F:51])([F:50])[C:12]1[CH:13]=[C:14]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[N:31][O:32][C:33]=2[CH:34]=O)=[O:28])[N:18]=[N:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:50][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[N:31][O:32][C:33]=2[CH2:34][NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:28])[N:18]=[N:17]1
Reactant: NCCN1CCOCC1
Reactant: O=Cc1onc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1)c1c(-c2ccccc2Cl)noc1CNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Add 4-(2-aminoethyl)-morpholine (129 mg, 0.992 mmol) to a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-3-(2-chloro-phenyl)-isoxazole-5-carbaldehyde (150 mg, 0.248 mmol) in 1,2-dichloroethane (2.5 mL). Then add NaBH(OAc)3 (157 mg, 0.744 mmol) and allow the mixture to stir at RT. After 3 h., quench the reaction with water and extract with EtOAc (2×50 mL). Dry the organic layer over MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to provide the title compound (61% yield) as a brown oil. MS (ES) 720.1 (M++1); TLC Rf=0.1 (EtOAc).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:24]([CH:20]3[C:21]([CH3:23])([CH3:22])[C:19]3([CH3:27])[CH3:18])=[O:25])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)C(C(=O)c2c[nH]c3cc(S(C)(=O)=O)ccc23)C1(C)C
Yield: 12.9 %

Procedure:
The 6-(methylsulfonyl)-1H-indole (Apollo Scientific, 1.0 g, 5.1 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.1 mL, 6.1 mmol), zinc chloride (1.0 M solution in Et2O, 6.1 mL, 6.1 mmol) and the product of Example 1A (7.7 mmol) were processed as described in Example 1B to provide the title compound (0.21 g, 0.66 mmol, 13% yield). MS (DCI/NH3) m/z 378 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[ClH:43].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18]S([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:38][CH2:39][N:40]([CH2:18][C:16]3[N:17]=[C:12]([C:4]4[S:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[C:2](=[O:1])[N:3]=4)[CH:13]=[CH:14][CH:15]=3)[CH2:41][CH2:42]2)=[CH:33][CH:32]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(CN3CCC(O)(c4ccc(Cl)cc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-(4-chlorophenyl)-4-hydroxypiperidine (0.20 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethylacetate to give the titled compound (0.20 g, 49%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Cl:29][C:30]1[CH:31]=[C:32]([S:38](Cl)(=[O:40])=[O:39])[C:33]([F:37])=[CH:34][C:35]=1[F:36]>O1CCCC1>[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([S:38]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)(=[O:40])=[O:39])[CH:31]=1
Reactant: COc1ccc(CNc2ncccn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
A solution of (2,4-dimethoxybenzyl)-pyrimidin-2-yl-amine (Preparation 38, 736 mg, 3 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C. before the addition of lithium(hexamethyldisilazane) (1M solution in tetrahydrofuran, 3.30 mL, 3.30 mmol). The reaction was allowed to warm to 0° C. for 30 minutes before cooling again to −78° C. The resulting solution was added to a solution of 3-chloro-4,6-difluorobenzenesulfonyl chloride (890 mg, 3.6 mmol) in tetrahydrofuran (10 mL) at −78° C. After 30 minutes at this temperature the reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography (50-100% dichloromethane in heptane gradient elution) to afford the title compound as a white solid (260 mg, 19%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:19][C:20](=[O:22])[CH3:21])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[NH:23]([C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([N+:36]([O-:38])=[O:37])[CH:28]=1)=[O:26])[NH2:24].Cl.O>CN(C=O)C>[C:20]([O:19][C:5]1[C:4]([C:1](=[N:24][NH:23][C:25]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([N+:36]([O-:38])=[O:37])[CH:28]=2)=[O:26])[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Reactant: NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)=NNC(=O)c2ccc(C(=O)O)c([N+](=O)[O-])c2)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of acetic acid 4-acetyl-2-(4-tert-butylphenyl)thiophen-3-yl ester (63.3 mg, 0.2 mmol) and 4-hydrazinocarbonyl-2-nitrobenzoic acid (54.0 mg, 0.24 mmol) in DMF (1 mL) was added 12 M aqueous HCl solution (16.7 μL, 0.2 mmol). The reaction mixture was stirred overnight, and then water was added. The precipitated solid was collected by filtration and washed with water and CHCl3 to give product as a pale yellow solid (29.1 mg, yield 28%).
Reaction SMILES: C([O:8][C:9]([C@@H:11]([N:27]([C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[NH:45][N:44]=[N:43][N:42]=2)=[CH:31][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(OCC1C=CC=CC=1)=O)=[O:10])C1C=CC=CC=1>CO.[Pd]>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([N:27]([C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[NH:45][N:44]=[N:43][N:42]=2)=[CH:31][CH:30]=1)[C:9]([OH:10])=[O:8]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](CCCCN)C(=O)O

Procedure:
170 mg of (S)-N-(1-benzyloxycarbonyl-5-benzyloxycarbonylamino-pent-1-yl)-N-pentanoyl-N-[2 '-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine are dissolved in 5 ml of methanol. The solution is treated with 170 mg of palladium/carbon (10%) and the mixture is hydrogenated to saturation under normal pressure and at room temperature. The mixture is filtered over Hyflo and the filtrate is evaporated, yielding the pure (S)-N-(5-amino-1-carboxy-pent-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of a white foam [MS (FAB): m/z=465, (M+H)+ ].
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:22]([CH3:24])[CH3:23])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:25][CH2:26][CH3:27].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:22]([CH3:24])[CH3:23])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:25][CH2:26][CH3:27]
Reactant: CCOc1c(/C(=C(/F)CO)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(=C(/F)C=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-4-methyl-pent-2-en-1-ol (Compound A-138, 140 mg, 0.32 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4 methylmorpholine N-oxide (94 mg, 0.80 mmol) were reacted in acetonitrile and dichloromethane to give the title compound as a white solid after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [Br-].[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]([CH3:33])=[N+:18]([CH2:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:34]OC(OC)N(C)C>CN(C=O)C>[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([C:22]([C:23](=[O:24])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=5)=[CH:34][CH:33]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: Cc1c(C(=O)NCC23CC4CC(CC(C4)C2)C3)ccc[n+]1CC(=O)c1cccc(C#N)c1
Reactant: COC(OC)N(C)C
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)c2ccc3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccn23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[(adamantan-1-ylmethyl)carbamoyl]-1-[2-(3-cyanophenyl)-2-oxoethyl]-2-methylpyridinium bromide (400 mg, 0.81 mmol) and N,N-dimethylformamide dimethyl acetal (0.22 mL, 1.62 mmol) in DMF (2.0 mL) is stirred at 110° C. for 3 h. The mixture is concentrated in vacuo and purified by column chromatography (gradient from CH2Cl2 to 10% EtOAc/CH2Cl2) to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (1H, d), 8.53 (1H, t), 8.15 (1H, m), 8.05 (2H, m), 7.74 (1H, t), 7.66 (1H, dd), 7.44 (1H, d), 7.22 (1H, t), 6.95 (1H, d), 3.01 (2H, d), 1.93 (3H, s), 1.63 (6H, m), 1.52 (6H, s). Mass spec. (438.19, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[C:10]([C:14]([OH:16])=O)[N:11]([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[C:10]([C:14]([N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:22]3)=[O:16])[N:11]([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2cccc(Br)c2)nn(C)c1C(=O)O
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(C(=O)c2c(C)c(-c3cccc(Br)c3)nn2C)C1
Yield: 77 %

Procedure:
In analogy to the procedure described in example 12D), 5-(3-bromo-phenyl)-2,4-dimethyl-2H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 77% yield as light yellow viscous oil. MS: 419.0 (MH+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([O:18]C)[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2Cl)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1Cl)c1ccc(O)c(Cl)c1Cl

Procedure:
The procedure of Example 24b is repeated except that 68 g of 2,3-dichloro-4-methoxy-2'-chlorobenzophenone is combined with 58.6 g of AlCl3 in 500 ml of benzene. The resultant product is recrystallized from toluene to yield 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone, mp 74°-77° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: O=Cc1c(O)c(O)cc2ccccc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1c(O)c(O)cc2ccccc12)c1cc2ccccc2cc1O
Yield: 18 %

Procedure:
Following the general procedure of Example 1, condensation of 2, 3-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded a yellow crystal (18%) [recrystallized from dioxane/H2O (1:1, v/v)]: mp>285° C.; 1H NMR d 13.16 (br s, 1 H), 12.27 (br s, 1 H), 11.30 (br s, 1 H), 9.74 (br s, 1 H), 9.57 (s, 1 H), 8.53 (s, 1 H), 8.17 (d, 1 H, J=8.2 Hz), 7.95 (d, 1 H, J=8.2 Hz), 7.79 (d, 1 H, J=8.0 Hz), 7.70 (d, 1 H, J=7.7 Hz), 7.54 (t, 1 H, J=7.4 Hz), 7.42-7.25 (m, 5 H); HRMS Calcd for C22H16N2O4 :372.1110, found 372.1103; Anal. (C22H16N2O4H2O) C, H, N.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[S:17][CH3:18].[C:19](=[O:21])=[O:20].O>O1CCCC1.C(OCC)C>[F:6][C:7]1[C:8]([S:17][CH3:18])=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:11][C:12]=1[C:19]([OH:21])=[O:20]
Reactant: CSc1c(F)cccc1C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(C(F)(F)F)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under an atmosphere of inert gas, 27.5 ml (1.6 M in hexane, 44 mmol) of n-butyllithium were added dropwise to a solution, cooled to −78° C., of 7.98 g (38 mmol) of 1-fluoro-2-methylthio-3-(trifluoromethyl)benzene in 60 ml of anhydrous tetrahydrofuran, where the temperature of the reaction mixture should not exceed −65° C. The mixture was stirred at −78° C. for 3 h, and at this temperature a carbon dioxide stream was then introduced such that the temperature of the reaction mixture did not exceed −45° C. The mixture was then warmed to RT and then once more cooled to 0° C. For work-up, water was added dropwise at this temperature until the precipitate formed had dissolved. Diethyl ether was added, and the organic phase was extracted three times with water. The combined aqueous phases were acidified with 10 percent strength hydrochloric acid. The aqueous phase was extracted repeatedly with dichloromethane, the combined organic phases were washed with saturated aqueous NaCl solution and dried over sodium sulfate and the filtrate was finally freed from the solvent. The crude product obtained in this manner was recrystallized from gasoline/ethyl acetate. This gave 6.8 g of 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoic acid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[CH:16]([CH2:26][C:27](OCC)=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1.CO.Cl>C1(C)C=CC=CC=1>[CH:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[CH:16]([CH2:26][CH2:27][OH:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC1c2ccccc2CCc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCCC1c2ccccc2CCc2ccccc21
Temperature: 0 °C

Procedure:
1120 ml of a 20 percent (v/v) solution of diisobutylaluminum hydride in toluene are added dropwise over a period of 1 hour while cooling to a solution of 160.36 g of ethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetate in 1 l of dry toluene, cooled in ice-water and stirred under argon. The solution is subsequently stirred at room temperature for 16.5 hours, cautiously treated while cooling with 20 ml of dry methanol, stirred for an additional 30 minutes and finally acidified with 1.5 l of 3N hydrochloric acid while cooling well. The organic phase is separated and washed with 1 l of water and the acidic-aqueous phase is back-extracted twice more with 2 l of ether each time. After washing the ethereal extracts with 1 l of water, the organic phases are combined, dried over magnesium sulfate and evaporated. The residue is taken up twice in 200 ml of dry toluene each time, the solutions obtained being in each case again evaporated to dryness. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil which crystallizes only slowly upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:27]S(O)(=O)=O.C([O-])(O)=O.[Na+].[ClH:37]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:26])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:37]
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reaction time: 6 h

Procedure:
An 18 mL-vial was charged with 2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile (12 mg, 0.033 mmol, synthesis of this compound was described in EXAMPLE 1). Concentrated H2SO4 (0.5 ml) was added at 0° C. The mixture was standing at room temperature for 6 hr. And then the mixture was added very slowly to NaHCO3 aq. at 0° C. The precipitate was collected and washed with water, dried. The product thus obtained was treated with 4N HCl in dioxane and the volatile material was removed under reduced pressure to give the desired product 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetamide as HCl salt (2.6 mg, 19% yield). MW=377.87. 1H NMR (CDCl3, 360 MHz) δ 7.83 (s, 1H), 7.69 (m, 1H), 7.18-7.30 (m, 7H), 5.77 (brs, 1H), 5.44 (brs, 2H), 3.58 (s, 2H), 3.08 (t, J=7.70 Hz, 2H), 2.83 (t, J=7.10 Hz, 2H), 2.21 (m, 2H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[CH:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:16](OCC)=[O:17].Cl>O1CCOCC1.O>[O:17]=[C:16]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:6]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc2c(c1)CCCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(=O)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetonitrile (21.48 mL, 411 mmol) was added to a stirred suspension of 60% NaH (7.05 g, 176 mmol) in dioxane (200 mL) and the resulting mixture was stirred at rt for 20 min. Solution of ethyl 5,6,7,8-tetrahydronaphthalene-2-carboxylate (12 g, 58.7 mmol) in dioxane (50 mL) was then added and the mixture was heated at reflux for 4 h. After cooling to rt, water followed by 1N HCl (100 mL) was added and the mixture was extracted twice with dichloromethane, dried (Na2SO4), filtered and concentrated to afford 3-oxo-3-(5,6,7,8-tetrahydronaphthalen-2-yl)propanenitrile as dark solid. A mixture of this syrup and hydrazine hydrate (2.77 mL, 88 mmol) in ethanol (200 mL) was refluxed for 16 h. The reaction mixture was then cooled to rt and concentrated in vacuo. The resulting crude was diluted with dichloromethane and washed with water, dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (5-10% CH2Cl2/MeOH) to afford desired 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6.1 g, 28.6 mmol, 48.7% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J=3.5 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 5.89 (s, 1H), 4.14 (br. s., 3H), 2.88-2.75 (m, 4H), 1.83 (dt, J=6.1, 3.4 Hz, 4H). LCMS (M+H)=214.2.