Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>C1COCC1>[Br:14][C:15]1[C:16]([CH3:1])=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a cold solution of diethyl malonate (2.2 mL, 14.5 mmol) in THF (30 mL) was added NaH (0.58 g, 60% in mineral oil) over 5 minutes. 3-Bromo-2-chloro-5-nitropyridine (3.13 g, 13.15 mmol) was added in 4 portions over 15 minutes. The reaction mixture was warmed to room temperature and THF was removed under reduced pressure. The mixture was heated at 115° C. for 75 minutes. After the reaction mixture was cooled to room temperature, H2SO4 (6.0 M, 17 mL) was added and the mixture was heated at 110° C. overnight. It was cooled to 0° C. and a KOH solution (25%) in water was added until pH=7.0. The reaction mixture was kept at 0° C. for 30 min. The crude product was collected by filtration and washed with cold water. dichloromethane (100 mL) was added to the solids and stirred at r.t. for 30 min. The solid was filtered off and the filtrate was concentrated to 30 mL. Petroleum ether (60 mL) was added and the solid was filtered off and the filtrate was concentrated to give the product as a red solid (2.3 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH:44]=[CH:45][CH:46]=O)[C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)#[N:27].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:46][CH:45]=[CH:44][C:30]3[C:31]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)=[CH:32][CH:33]=[C:28]([C:26]#[N:27])[CH:29]=3)=[CH:17][C:16]=2[C:22]([F:25])([F:23])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
To a mixture of 4-[(N-(t-butoxycarbonyl)piperidin-4-yl)oxy]-3-trifluoromethylbenzenamine (4.9 g) and 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (4 g) in MeOH (80 mL) was added acetic acid (0.73 g). The resulting solution was stirred at ambient temperature for 15 minutes and then NaCNBH3 was added. The resulting solution was stirred at ambient temperature for 1 hour and concentrated. The residue was taken up in 100 mL of aqueous NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried, concentrated and purified on silica gel column (ethyl acetate/hexane, 3:7) to afford 5.7 g of 4-(N (t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine as a yellow oil.
Reaction SMILES: CO.S(C1C=CC(C)=CC=1)(O[CH:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])(=O)=O.[CH3:25][NH:26][CH3:27].C(OCC)C>C(Cl)(Cl)Cl>[CH3:8][CH:7]([N:26]([CH3:27])[CH3:25])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(CCOc1ccccc1)N(C)C
Yield: 66 %

Procedure:
To 60 ml of absolute methyl alcohol were added 10 g of 4-phenoxy-2-butyl tosylate and 5.93 g of dimethylamine. The mixture was reacted in a sealed tube for one hour at 125° C. After the reaction solution was condensed under reduced pressure, 100 ml of diethyl ether was added into the solution and the solution was separated into the diethyl ether solution and 20% aqueous sodium hydroxide solution. The ether layer was dried over anhydrous sodium sulfate, and then the ether was removed under reduced pressure therefrom. The residue thus obtained was subjected to an alumina-column chromatography using chloroform as the developing solvent to give 3.98 g of 1-methyl-3-phenoxypropyldimethylamine in a yield of 66%.
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.O>[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:34][CH:35]=1)[C:25]([OH:27])=[O:26])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(Cl)cc(Cl)c1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C(Nc1ccc(C(=N)NO)cc1)C(=O)O
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
3.7 g of finely powdered lithium carbonate were added to a solution of 1.96 g of methyl (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate (see Example 276.2) in 200 ml of THF and 100 ml of water. The suspension was stirred for 8 hours at 55-60° C. The reaction mixture was then concentrated and the aqueous suspension remaining was neutralized with 100 ml 1N HCl. The precipitate was filtered off, washed with water and dried overnight at 50° C. in a high vacuum. There were obtained 1.59 g of (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid; MS (ISP) m/z 484.3 (M+H)+, 506.2 (M+Na)+.
Reaction SMILES: Cl.[CH:2]1[C:7]([CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([F:13])[CH:3]=1.[CH3:14]O>>[NH2:12][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([F:13])=[CH:3][CH:2]=1)[C:9]([O:11][CH3:14])=[O:10]
Reactant: NC(C(=O)O)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl (g) was bubbled into a solution of 4-fluoro-DL-phenylglycine (810 mg, 4.79 mmol) in methanol (20 mL) for 5 min at 0° C. The reaction warmed to ambient temperature and stirred for 18 h. The mixture was concentrated to give the title compound (1 g). MS 183.9 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([CH:19]=[O:20])[C:3]=1[Cl:21].CC(=CC)C.O.O.[OH:29]P([O-])([O-])=O.[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:29])=[O:20])[C:3]=1[Cl:21]
Reactant: O=P([O-])([O-])O
Reactant: COc1c(Cl)ccc(-c2nc(C=O)c(Cl)c(N)c2F)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-pyridine-2-carbaldehyde (400 mg, 1.201 mmol) and t-butanol (6 mL). Rapid stiffing and warming with a heat gun failed to dissolved all of the aldehyde. Additional t-butanol (2 mL) was added, but still failed to form a homogeneous solution. The mixture was treated with H2O (2 mL), 2-methyl-2-butene (1 mL), sodium phosphate dibasic dihydrate (Na2HPO4; 341 mg, 2.402 mmol, 2 equiv) and finally sodium chlorite (326 mg, 3.60 mmol, 3 equiv) was added in one portion. The mixture was stirred at room temperature for 5 min and then placed in an oil bath and heated to 85° C. After stiffing at 85° C. for 60 min, the reaction mixture finally became a light yellow, homogenous solution. After stirring at 83° C. overnight (12 h), an aliquot of the reaction mixture was partitioned between EtOAc and 1 molar (M) hydrochloric acid (HCl) and analyzed by HPLC and LC-MS. HPLC analysis showed that all of the starting material had been consumed and one major, slightly more polar product formed along with multiple minor products. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream-colored solid. The crude material was stirred with Et2O (5 mL). After stiffing for 3 h, the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, 83%) was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.47 (dd, J=8.5, 1.4 Hz, 1H), 7.31 (dd, J=8.4, 7.1 Hz, 1H), 7.04 (s, 2H), 3.93 (s, 4H); 19F NMR (376 MHz, DMSO-d6) δ −129.10 (d, J=28.3 Hz), −138.56 (d, J=28.4 Hz); ESIMS m/z 349 ([M+H]+), 347 ([M−H]−).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[Br:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:14][C:11]1([CH3:13])[CH2:10][C:9]2[CH:15]=[C:5]([S:2]([NH:1][C:18](=[O:19])[CH:17]([Br:16])[CH3:21])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[O:12]1
Reactant: CC1(C)Cc2cc(S(N)(=O)=O)ccc2O1
Reactant: CC(Br)C(=O)Cl
Product: CC(Br)C(=O)NS(=O)(=O)c1ccc2c(c1)CC(C)(C)O2
Yield: 87.7 %

Procedure:
In a manner similar to Step C of Example 9, the reaction of 4.0 g (0.017 mole) of 5-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran with 7.0 mL (0.069 mole) of 2-bromopropionyl chloride produced 5.4 g of N-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)sulfonyl-2-bromopropionamide as a solid (mp 125°-128° C.).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1>>[CH3:12][C:4]1[C:5]([C:9]([N:18]2[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]2)=[O:11])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Yield: 72.1 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) was reacted with cis-2,6-dimethylpiperazine (2.66 g, 14.36 mmol) to give 2.27 g (72% yield) of 3,5-dimethyl-4-[(3R,5S)-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrole-2-carbaldehyde using General Amidation Procedure 1. 1H-NMR (360 MHz, diemthylsulfoxide-d6) δ 11.84 (br s, 1H, NH), 9.51 (s, 1H, CHO), 4.30 (br s 1H, NH), 2.50 (m, 4H, 2×CH2), 2.28 (m, 8H, 2×CH3 and 2×CH), 0.96 (m, 6H, 2×CH3). MS m/z 264 [M+1].
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[CH2:6][OH:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C)ccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(C)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of methyl 2-allyl-4-methylbenzoate (220 mg, 1.156 mmol) in THF (2 mL) was added LAH (2.313 mL, 2.313 mmol) and the reaction mixture was stirred at rt for 1 h. It was then added NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (2-allyl-4-methylphenyl)methanol (150 mg, 0.925 mmol, 80% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ 7.31-7.25 (m, 1H), 7.10-7.03 (m, 2H), 6.03 (ddt, J=16.9, 10.4, 6.3 Hz, 1H), 5.13-5.00 (m, 2H), 4.69 (d, J=5.2 Hz, 2H), 3.48 (d, J=6.3 Hz, 2H), 2.36 (s, 3H), 1.53 (t, J=5.7 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[N:10]=[C:9]1[NH2:20])=O)(C)(C)C.[N:21]([CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])=[N+:22]=[N-:23]>>[NH2:20][C:9]1[NH:8][CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[N:23]=[N:22][N:21]([CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:19]=2)[N:10]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccccc1
Product: Nc1nc(CCCCCc2cn(CC(=O)Nc3ccccc3)nn2)c[nH]1
Yield: 52.4 %

Procedure:
Following the general procedure, 2-amino-4-hept-6-ynyl-imidazole-1-carboxylic acid tert-butyl ester (0.075 g, 0.270 mmol) was reacted with 2-azido-N-phenyl-acetamide (0.072 g, 0.410 mmol) and afforded 0.050 g (51% yield) of 2-{4-[5-(2-amino-1H-imidazol-4-yl)-pentyl]-[1,2,3]triazol-1-yl}-N-phenyl-acetamide hydrchloride. 1H NMR (400 MHz, CD3OD) 8.53 (s, 1H), 7.59 (d, J=7.6, 2H), 7.31 (t, J=7.2, 2H), 7.11 (t, J=7.2, 1H), 6.50 (s, 1H), 5.62 (s, 2H), 3.96 (s, 1H), 2.89 (bs, 2H), 2.50 (t, J=6.8, 2H), 1.79 (bs, 2H), 1.66 (bs, 2H), 1.45 (bs, 2H); 13C NMR (100 MHz, CD3OD) δ 164.3, 148.6, 139.2, 130.1, 128.9, 125.9, 121.2, 109.8, 55.7, 28.9, 25.3, 24.7; HRMS (ESI), calculated for C18H23N7O (MH+) 353.1964. Found 353.1968.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:11])=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1ccc(Cl)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.00 g (11.7 mmol) 2-(6-chloropyridin-3-yl)-acetamide in 50 mL THF at 0° C. are added 12.9 ml LAH (c=1 mol/l in THF) by a dropping funnel. Cooling is removed and the reaction mixture is stirred for 1 h at r.t., then 8 ml LAH (c=1 mol/l in THF) are added and the reaction mixture is stirred at r.t. over night. The reaction is carefully quenched by the addition of 2 ml of an aq. NaHCO3 solution (10%). The mixture is filtrated and the solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH2:32])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]=2[CH:31]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH:32][S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:13]=2[CH:31]=1
Reactant: COC(=O)CCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
5-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:4]=1)[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: CCc1nc(-c2ccccc2OC)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc(Cl)cc(-c2ccccc2OC)n1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution of 2-ethyl-6-(2-methoxy-phenyl)-3H-pyrimidin-4-one (1.1 g, 4.9 mmol) and phosphorous oxychloride (3.0 mL, 32 mmol) was refluxed for four hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo and the resultant residue was diluted with dichloromethane. The organics were washed with ice-water. After extraction of the aqueous layer with dichloromethane the combined organics were washed with brine and dried over sodium sulfate. Following Si gel chromatography (1:5 ethyl acetate:hexanes) 0.91 g (74%) of the title compound was isolated as a pale yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccccc2F)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1ccccc1[C@@H]1CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 75.3 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(2-fluorophenyl)piperidin-1-yl]methanone (25 mg, 0.073 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 18 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:21].O1CCOCC1>O1CCOCC1>[ClH:21].[CH3:1][S:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(SC)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of O1-tert-butyl O4-ethyl 4-methylsulfanylpiperidine-1,4-dicarboxylate (0.23 g, 7.75 mmol) in 1,4-dioxane (20 mL) was added HCl-dioxane (4 M, 15 mL) solution and the mixture stirred at rt for 30 min. After completion of reaction (by TLC), the solvent was evaporated to obtain a brownish solid material (0.17 g) that was carried forward to the next step without further purification. MS: 204.10 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[N:5]=1)(=[O:3])[CH3:2].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N(CC(O)=O)C=1)(=O)C>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([CH2:17][C:18]([OH:20])=[O:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2cc1OC
Agent: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COc1cc2c(C(C)=O)nn(CC(=O)O)c2cc1OC

Procedure:
The title compound was prepared from tert-butyl 2-(3-acetyl-5,6-dimethoxy-1H-indazol-1-yl)acetate in a similar manner as described in step C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 279 [M+H]+; tR (HPLC conditions k): 2.73 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Temperature: 80 °C

Procedure:
A mixture of 51 mg (0.191 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (CAS 1208984-79-5) and 140 ul (1.91 mmol) thionylchloride in toluene (0.5 ml) was heated in a 80° C. oil bath for 4 hours. The solvent was removed in vacuo to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:12]=[C:13]([C:19](O)=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:28][N:29](C)[CH2:30]CCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:12]=[C:13]([C:19]([N:29]([CH3:30])[CH3:28])=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:16])=[O:17])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)O)nn12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)N(C)C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid (40.0 mg), diemthylamine hydrochloride (12.4 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25.2 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) was stirred for 3 hours at room temperature. The mixture was partitioned between ehtyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10×3 mL), saturated sodium bicarbonate (10 mL), and brine, dried over magnesium sulfate, and evaporated to give 4-(3-cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamide as an yellow solid (43.4 mg, 101%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.C1C(=O)N([I:25])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]=1[I:25]
Reactant: Fc1ccc(-c2cn3c(n2)CCCC3)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCCC3)c(F)c1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (3.25 g, 13.9 mmol, prepared using General Procedure R from Example #8, Step A with 2-iminopiperidine hydrochloride), NIS (3.12 g, 13.9 mmol), and DMF (35 mL) was stirred at ambient temperature. After stirring overnight, the reaction mixture was partitioned between Et2O (400 mL) and water (200 mL). The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient from 100:0 to 0:100) to give the title compound (3.44 g, 69%). LC/MS (Table 1, Method a) Rt=3.32 min; MS m/z: 361.0 (M+H)+.
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[NH3:43]>CC(N(C)C)=O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][S:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:41])/[C:20]/2=[CH:19]\[C:16]1[NH:15][C:14]([CH3:42])=[C:13]([C:11]([NH2:43])=[O:12])[C:17]=1[CH3:18])(=[O:31])=[O:30]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: N
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added ammonia (2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated and triturated with methanol to give the titled compound as a yellow solid.