Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[CH3:16][C:17]1([CH3:24])[CH2:22][NH:21][C:20]([NH2:23])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[CH3:16][C:17]1([CH3:24])[CH2:22][N:21]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:20]2[NH:19][CH2:18]1
Reactant: CC1(C)CN=C(N)NC1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Yield: 80.5 %

Procedure:
A mixture of 5.9 g (30.55 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate, 5.0 g (30.55 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (prepared by analogy to U.S. Pat. No. 4,262,122) and 6.33 g (45.82 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 12 h. The cooled suspension was filtered and the solvent removed by evaporation. The residue obtained was dissolved in dichloromethane and washed with water. The organic phase was dried and evaporated to give 6.30 g (80%) of product as a beige solid. Mp.: 152-154° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3].CCOCC.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:2]([CH3:3])([C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1]
Reactant: CCCCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCC(=O)C(C)(C)C
Yield: 67 %

Procedure:
2,2-dimethyl-nonan-3-ol, available as a concentrated solution in ether (ca. 0.23 moles, cf. previous procedure), was dissolved in ca. 350 mL CH2Cl2 in a 500 mL round bottom flask. With vigorous stirring and external cooling, pyridinium chlorochromate (PCC, 76.6 g, 0.355 mol) was added slowly. The reaction mixture turned black and began to warm. The reaction was stirred overnight at room temperature, and the supernatant was decanted from a black sludge which had formed. The sludge was extracted with ca. 40 mL of hexane, which was combined with the CH2Cl2 solution. This mixture was applied directly to a 100 g silica gel column, and eluted first with CH2Cl2/hexane and then with 10% ethyl acetate in hexane to yield 35.8 g crude, green-colored product. This material was rechromatographed; elution with hexane and careful evaporation at 25° C. on a rotary evaporator yielded 26.1 g 2,2-dimethyl-nonan-3-one (67% yield). 1H NMR (500 MHz, CDCl3), δ (ppm): 2.47 (t, 2H), 1.28 (br, 8H), 0.89 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H]2CN(C(OC(C)(C)C)=O)[CH2:18][C@H:4]2[NH:3]1.Cl.O1CCO[CH2:29][CH2:28]1>C(OCC)C>[CH2:28]([N:3]([CH2:4][CH3:18])[C:2](=[O:1])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]([F:13])([F:14])[F:15])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (50 mg, 0.14 mmol) in 1 mL of 1,4-dioxane was added 4 mL of 4 N HCl in dioxane. The reaction was allowed to stir for 4 h and then was diluted with diethyl ether. A solid slowly settled out of solution. The solvents were decanted and the remaining solid was triturated twice with diethyl ether and dried in vacuo to afford 35 mg (85%) of the title compound of Example 1 as an off-white solid. 1H NMR (DMSO-D6): δ 9.8 (broad s, 1H), 9.6 (broad s, 1H), 8.15 (s, 1H), 7.86 (d, 1H, J=7.1 Hz), 7.78-7.70 (m, 2H), 4.40-4.38 (m, 1H), 3.75-3.67 (m, 2H), 3.55-3.52 (m, 1H), 3.45-3.37 (m, 1H), 3.10-3.05 (m, 1H). LRMS (ESI): 257.16 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](I)[CH3:25]>>[C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:24][CH3:25])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCCN1CCCC(CO)C1)S(=O)(=O)c1ccccc1
Reactant: CCI
Product: CCOCC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (55 mg of 60% dispersion in oil) was washed with i-hexane and treated with tetrahydrofuran (3 ml). [1-(4-Benzenesulfonyl-4-methyl-pentyl)-piperidin-3-yl]-methanol (95 mg, 0.28 mmol) was added and the mixture was stirred at room temperature for 10 min. Ethyl iodide (0.5 ml) was added to the mixture that was stirred for 5 hours. The reaction mixture was quenched with 25% ammonia and extracted into dichloromethane. The combined organic extract were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give to give the title compound.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])C.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1>C(O)(=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]2[C:27](=[CH:28][CH:29]=1)[NH:30][CH:4]=[C:5]2[CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Reaction time: 1 h
Yield: 64.6 %

Procedure:
4-[1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl]butanal diethyl acetal (11.6 g) was added with vigorous stirring to a solution of 4-bromophenylhydrazine hydrochloride (9.0 g) in 50% aqueous acetic acid (370 ml). The mixture was heated on a steam bath for 4 hours and was then diluted with water, while still hot, to 1 l. The mixture was cooled and an orange yellow precipitate was filtered off and dried in vacuo. The solid was boiled in ethanol (250 ml) for 1 hour and residual solid filtered off and dried to afford the title compound as a yellow solid (9.5 g) m.p. 206°-209° C. Crystallisation of a portion of this solid (0.5 g) from ethanol (25 ml) gave a sample (0.25 g) m.p. 208°-212° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1>>[CH2:1]([C:4]1[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)[C:7]2[CH:9]=[C:10]([N:14]3[C:15](=[O:24])[C:16]4=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]4[C:18]3=[O:19])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Product: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and methyl 4'-bromomethyl-biphenyl-2-carboxylate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25])=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=4[C:24]#[N:25])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: N#Cc1ccccc1C=O
Product: N#Cc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 2-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:4][C:5]1([CH3:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC1(C)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A mixture of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate (3.10 g, 12.1 mmol) and 4N HCl/dioxane (15 mL, 60.0 mmol) was stirred at rt for 3 h. It was then concentrated in vacuum to obtain 2.2 g (95%) of 4-(allyloxy)-4-methylpiperidine hydrochloride as a light brown solid. 1H NMR (500 MHz, CD3OD) δ 6.02-5.92 (m, 1H), 5.33 (dd, J=17.2, 1.7 Hz, 1H), 5.15 (dd, J=10.6, 1.7 Hz, 1H), 3.96 (dt, J=5.1, 1.6 Hz, 2H), 3.23-3.18 (m, 4H), 2.06 (dd, J=15.3, 2.5 Hz, 2H), 1.77-1.69 (m, 2H), 1.31-1.28 (s, 3H). Free base (brown solid) is obtained by stirring HCl salt with aq Na2CO3 and extracting with DCM.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[Si:21]([O:28][C:29]1[C:36]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:35]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:34]=[CH:33][C:30]=1[CH:31]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C1COCC1>[Si:21]([O:28][C:29]1[C:30](/[CH:31]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:33][CH:34]=[C:35]([O:45][Si:46]([C:49]([CH3:50])([CH3:52])[CH3:51])([CH3:48])[CH3:47])[C:36]=1[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (0.89 mL, 2.23 mmol, 2.5 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.96 g, 1.83 mmol) in THF (10 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70° C. and a solution of 31 (0.93 g, 1.88 mmol) in THF (4 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (1.5 g). Purification by column chromatography (SiO2; 5:95 TBME:cyclohexane+1% Et3N) gave 32 compound (0.6 g, 50%) as a 86:14 mixture of Z:E isomers:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)=[CH:9][C:8]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:29].CCOC(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)([OH:20])[C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)=[CH:9][C:8]=1[C:28](=[O:29])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:4]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(N)c(C(=O)c2cccc(Cl)c2)c1
Reactant: O=C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CBr)c(C(=O)c2cccc(Cl)c2)c1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
Bromo-acetyl bromide (0.0138 mol) was added slowly at 5° C. to a mixture of (±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (prepared as described in WO 97/21701) (0.0137 mol) in acetic acid (60 ml). The mixture was stirred for 15 min and poured out into EtOAc and NaOH 0.5N. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 7.3 g (93%) of 2-bromo-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide (intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[C@@H:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27]1)=[O:22]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Reactant: CN1CCNC[C@@H]1Cc1ccccc1
Product: CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(Cl)cc23)C[C@@H]1Cc1ccccc1

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12) and (2S)-1-methyl-2-(phenylmethyl)piperazine (Description 35) according to the method of Description 25. 1H NMR (400 MHz, CDCl3) mixture of two amide rotamers; δ7.56-6.98 (12H, m), 4.09, 3.93 (total 1H, each d, J 13.1 Hz), 3.53, 3.47 (total 3H, each s), 3.20-1.98 (12H, m), and 2.39, 2.38 (total 3H, each s). m/z (ES+) 520, 522 (M+1).
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:33])[NH:7][C:8]2[CH:31]=[CH:30][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[N:26]=[C:25]([C:27]([O-:29])=O)[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:32])[CH2:4][CH2:3][CH2:2]1.[Na+].C(N(CC)CC)C.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:42]([NH:46][C:27](=[O:29])[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]3[CH:30]=[CH:31][C:8]([NH:7][C:6]([NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:33])=[C:9]([F:32])[CH:10]=3)[CH2:15][CH2:16]2)[N:26]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)[O-])n3)CC2)cc1F)NC1CCC1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)n1
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Sodium 6-((4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)-picolinate (100 mg, 0.209 mmol), triethylamine (66 mg, 0.693 mmol, 0.091 mL) and tert-butylamine (32 mg, 0.435 mmol) were combined and stirred at room temperature in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (208 mg, 0.326 mmol, 0.194 mL, 50% solution in ethyl acetate) was added dropwise and the reaction allowed to stir for 1 hour. The reaction mixture was concentrated at reduced pressure, the resulting residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the title compound (24 mg). MS (ESI) m/z 511.6 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([CH2:28][OH:29])[CH2:3][NH:4][C:5]([C:7]1[C:8](=[O:27])[N:9]([CH3:26])[C:10]2[C:15]([C:16]=1[OH:17])=[N:14][CH:13]=[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:11]=2)=[O:6].[OH-].[Na+:31]>>[OH:1][C@@H:2]([CH2:28][OH:29])[CH2:3][NH:4][C:5]([C:7]1[C:8](=[O:27])[N:9]([CH3:26])[C:10]2[C:15]([C:16]=1[O-:17])=[N:14][CH:13]=[C:12]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:11]=2)=[O:6].[Na+:31]
Reactant: Cn1c(=O)c(C(=O)NC[C@@H](O)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c(C(=O)NC[C@@H](O)CO)c([O-])c2ncc(Cc3ccc(F)cc3)cc21
Yield: 94 %

Procedure:
In a manner similar to that described in example 474, from N-[(2R)-2,3-dihydroxypropyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (395 mg, 0.985 mmol described in example 516) and 1 N sodium hydroxide (0.99 mL) was prepared sodium 3-({[(2R)-2,3-dihydroxypropyl]amino}carbonyl)-7-[(4-fluorophenyl)methyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (390 mg, 94% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.61 (s, 1 H), 8.17 (s, 1 H), 7.60 (s, 1 H), 7.33-7.29 (m, 2 H), 7.11-7.06 (m, 2 H), 4.85 (m, 1 H), 4.57 (m, 1 H), 4.02 (s, 2 H), 3.50 (m, 1 H), 3.38 (s, 3 H), 3.40-3.25 (m, 3 H), 3.16 (m, 1 H); MS m/z 402 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:1]/[C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(Cl)cc2)s1
Yield: 67 %

Procedure:
A solution (1.74 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate (prepared as described in example 1, step 1) in MeOH, was treated with 4-chlorobenzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution, a catalytic amount of pyrrolidine (0.10 eq.) was added. The reaction mixture was heated to reflux overnight. After cooling down, evaporation of the solvent gave a residue that was triturated with petroleum ether/Et2O and filtered to afford the title compound title compound (67%) as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCCCl)Cc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)(=O)Cc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 5-benzylsulfonylpentyl chloride were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-benzylsulfonylpentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=[O:10].[Na+].OOS([O-])=O.[K+]>CP(CCP(C)C)C.CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([OH:10])[CH:5]=[C:4]([Cl:8])[CH:3]=1
Reactant: Clc1cccc(Br)c1
Reactant: O=C([O-])O
Agent: CP(C)CCP(C)C
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1cc(Cl)cc(Br)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To an airfree flask equipped with a stir bar, in a glove box, was added m-bromochlorobenzene (192 mg, 1.00 mmol), HBPin (200 mg, 1.56 mmol), (Ind)Ir(COD) (8.3 mg, 0.02 mmol), and dmpe (3.0 mg, 0.02 mmol). The flask was sealed, removed for the glove box, and stirred at 150° C. for 3 h. This material was used in next step without purification. To the crude material was added NaOH (1.5 mL of a 1.5M aqueous solution) and the resulting mixture was stirred for 5 minutes. To this was added NaHCO3 (0.73 g, 8.7 mmol) and acetone (3 mL). The mixture was cooled to 0° C. and OXONE (3.2 mL of a 0.33M aqueous solution) was added dropwise. The reaction mixture was stirred at 0° C. for 10 minutes and quenched with sodium bisulfite (2.0 g in 3 ml H2O). The grayish solution was diluted with ether (20 ml), and extracted with aq. 2 M HCl (1×25 ml). The aqueous layer was separated from the organic layer and extracted with ether (2×25 ml). Combined organic layers were washed with water (2×25 ml), dried with MgSO4, and solvents removed under reduced pressure. Crude material was passed through silica plug eluting with CH2Cl2 to give 163.4 mg (78.8%) of 3-bromo-5-chlorophenol as a white solid. In a separate run under the same conditions with twice the scale, 301.2 mg (72.4%) of desired phenol was obtained. mp=68-69° C. 1H NMR (CDCl3, 300 MHz) δ 7.08 (t, J=1.65 Hz, 1H), 6.89 (dd, J=2.2, 1.65 Hz, 1H), 6.78 (dd, J=2.2, 1.65 Hz, 1H), 4.83 (s, 1H). 13C NMR (CDCl3, 125 MHz) δ 156.6, 135.7, 124.1, 122.9, 117.4, 115.0. FT-IR (KBr) 3221, 3159, 3090, 3046, 2927, 2856, 2793, 2659, 2492, 1577, 1486, 1458, 1426, 1376, 1359, 1286, 1239, 1214, 1088, 913, 859, 840, 778, 666 cm−1. MS (rel. int.) m/z 208 (100), 206 (82), 127 (26), 99 (37), 63 (22). Anal. Calcd for C6H4BrClO: C, 34.74; H, 1.94; N, 0.00. Found: C, 35.08; H, 2.03; N, 0.07.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C@:11]12[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][CH2:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CN(C=O)C>[Br:8][C:24]1[C:23]2[N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:21]=[CH:20][C:19]=2[CH:18]=[C:17]2[C@@:11]3([CH2:9][CH3:10])[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]3[CH2:13][CH2:14][CH2:15][C:16]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Temperature: 25 °C
Yield: 49 %

Procedure:
NBS (0.011 g, 0.064 mmol) was added to a solution of (3R,4aR,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.022 g, 0.049 mmol) in DMF (0.5 mL) and the mixture was heated to about 60° C. for about 3 h. After cooling to rt, the reaction was quenched with ice (5 g). Sat. Aq. Na2CO3 (10 mL) and EtOAc (20 mL) were added. The layers were separated and the organic layer was washed with water (10 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-27% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure. The residue was lyophilized to yield (3R,4aR,12bS)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (46, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.013 g, 49% yield); LC/MS, method 2, Rt=3.13 min.; MS m/z: 525 and 527 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.90 (s, 1H), 7.57-7.50 (m, 2H), 7.38-7.30 (m, 2H), 5.56 (s, 1H), 3.56-3.44 (m, 1H), 3.03-2.88 (m, 1H), 2.43-2.18 (m, 2H), 2.16-1.66 (m, 7H), 1.64-1.38 (m, 4H), 0.68 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O>ClCCl.CS(C)=O.C(N(CC)CC)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(OC)c1ccc(C(O)Cc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29.16 g (0.183 mol) sulfur trioxide pyridine complex is added in portions to a solution of 33 g 1-[4-(dimethoxymethyl)phenyl]-2-phenylethanol in dichloromethane (540 ml), DMSO (140 ml) and triethylamine (25.5 ml) at 10° C. The mixture is slowly warmed to room temperature and stirred for 2 h. Water is added and the organic phase is separated, washed with 1 mol/l HCl, 3 times with 5% w/w sodium thiosulfate solution and saturated NaCl. The combined organic phases are dried over sodium sulfate and the solvens is evaporated. The residue is purified on a silica gel column chromatography (n-Hexan/EtOAc).