Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][C:8]2[N:9]([CH3:12])[C:10](=[O:11])[C:4]3[CH:3]=[C:2]([CH2:24][CH:23]=[CH2:22])[CH:21]=[N:20][C:5]=3[N:6]([CH2:18][CH3:19])[C:7]=2[N:16]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(C)nc1N2CC
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A solution of 8-bromo-5,11-dihydro-2,5-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (258 mg, 0.7 mmol) in DMF (7.4 mL) was degassed under reduced pressure for 20 min. Pd(PPh3)4 (43 mg, 0.04 mmol) was then added followed by allyltributyltin (0.3 mL, 0.85 mmol). After degassing under reduced pressure for 10 min, the mixture was heated to 100° C. for 1.5 h. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8:2) to give the title compound (184 mg, 98% yield) as a yellow solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:21][CH3:22])[CH:20]=1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:16]=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 100.4 %

Procedure:
A solution of 1-tert-butyl 1-piperazinecarboxylate (Sigma Aldrich, 3.37 g, 18.12 mmol), 5-fluoro-2-nitroanisole (Oakwood Products, West Columbia, S.C., 3.10 g, 18.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.31 mL, 36.2 mmol) in DMSO (11 mL) in a 20 mL glass microwave tube was sealed and heated in a heating block at 95° C. overnight (20 h). Upon cooling, the reaction mixture crystallized to a yellow solid. It was diluted with 150 mL of EtOAc, washed sequentially with 20 mL of water, 20 mL of NaHCO3 and brine (20 mL). The organic solution was dried over MgSO4 and concentrated affording tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (6.14 g, 18.20 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 359.9 (M+Na)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.96 (1H, d, J=9.2 Hz), 6.59 (1H, dd, J=9.4, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 3.97 (3H, s), 3.56-3.65 (4H, 3.45-3.52 (4H, m), 1.51 (9H, s). Pd/C (10 wt. %, dry basis, wet activated, 284 mm, 0.267 mmol) and tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (600 mg, 1.78 mmol) were treated with EtOH (30 mL) and allowed to stir under an atmosphere of hydrogen (balloon) for 23 h. The reaction mixture was filtered through an acrodisc (0.20 um), the resulting purple solution was then concentrated on the rotovap and then under vacuum overnight affording tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (539 mg, 1.76 mmol, 99% yield) as a purple film. m/z (ESI, +ve ion) 307.0/309.0 (M+H)+. 1H NMR (400 MHz, MeOH) δ ppm 6.71 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=2.3 Hz), 6.46 (1H, dd, J=8.3, 2.4 Hz), 3.85 (3H, s), 3.51-3.61 (4H, m), 2.92-3.02 (4H, m), 1.47-1.52 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[CH:12]([O:15][B:16]1[O:20][C:19](C)(C)[C:18]([CH3:24])([CH3:23])O1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:24][C:18]1([CH3:23])[CH2:12][O:15][B:16]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[O:20][CH2:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1B1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1-methylpyrazole (4.1 g, 50 mmole) in THF (100 mL) at 0° C. was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. over 1 hour. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organic fractions were washed with H2O (2×100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 1H), 6.75 (s, 1H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCCS(=O)(=O)c2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl]phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:36][CH2:37][S:38][CH3:39])[C@@H:18]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:19]([O:21]CC1C=CC(OC)=CC=1)[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:36][CH2:37][S:38][CH3:39])[C@@H:18]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)OCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of (2S,6R,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-7-isobutoxy-8-((4-methoxybenzyl)oxy)-6-(2-(methylthio)ethyl)nonanoate (536 mg, 0.941 mmol) and 0.85 mL H2O in CH2Cl2 (9.4 mL) at 0° C. (icewater bath) was added DDQ (214 mg, 0.941 mmol). The resulting dark mixture was stirred at 0° C. for 3 h, then another portion of DDQ (41 mg, 0.180 mmol) were added and the reaction was stirred for 1 h. The reaction was quenched with sodium hydroxide (NaOH; 1.3 ml of 1M aqueous, 1.3 mmol) and stirred for 10 min. The reaction was then diluted with H2O (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a red oil which was purified by column chromatography on SiO2 (5→35% acetone/hexanes gradient) to furnish the title product as a clear, colorless oil (353 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 5.02 (d, J=8.0 Hz, 1H), 4.31 (d, J=5.2 Hz, 1H), 3.95-3.83 (m, 1H), 3.74 (d, J=1.6 Hz, 3H), 3.36 (dd, J=8.5, 6.3 Hz, 1H), 3.22 (dd, J=8.5, 6.6 Hz, 1H), 3.05 (dd, J=5.6, 3.9 Hz, 1H), 2.58 (ddd, J=14.0, 8.7, 5.3 Hz, 1H), 2.47 (ddd, J=12.8, 8.3, 7.4 Hz, 1H), 2.10 (s, 3H), 1.96-1.68 (m, 4H), 1.68-1.49 (m, 3H), 1.45 (s, 9H), 1.39 (s, 4H), 1.21 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.7, 1.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.36, 155.36, 84.83, 79.93, 79.24, 68.10, 53.20, 52.27, 38.01, 33.20, 33.05, 32.76, 30.90, 29.21, 28.83, 28.33, 22.83, 19.52, 19.46, 19.11, 15.43; ESIMS m/z 450.4 ([M+H]+), 472.4 ([M+Na]+).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27](C=C)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][Si:2]([CH3:21])([CH3:1])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])/[CH:15]=[CH:16]/[C:27]2[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C[Si](C)(C)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1
Reactant: C=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(/C=C/c1ccc(Cl)cc1)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1

Procedure:
As in reaction conditions of Example XIX Step 2, to 2.84 mL of toluene, the 0.016 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(II) was added, and the reaction was carried out between the 1-[(1-trimethyl siloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-vinyldisilazane obtained in Step 1 and 0.92 g 4-chlorostyrene. Product was separated under the purification conditions of Example XII. The product, 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-[(E)-4-chlorostyryl]disilazane, was obtained with a total yield of 86% pure product in the form of an oily, yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 525.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>O>[ClH:1].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCCC2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N2CCCC2)CC1

Procedure:
29.0 Grams of 4-chloro-3-pyrrolidinosulfonylbenzoic acid (0.1 mole) were heated with 50 ml of N-methylpiperazine for 4 hours under reflux. Subsequently the reaction solution was introduced into 0.3 l of water, and the pH value of the mixture was adjusted to 3.0 by means of 5N HCl. After having been allowed to stand over night at room temperature, the precipitate was suction-filtered, recrystallized from water and dried at 100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]acetamide was oxidized using a procedure similar to that described in Example 1. Chromatography, with ethyl acetate:dichloromethane (gradient, 15:85, 30:70) as the eluent, gave 2-[5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl]acetamide as a white solid; 300 MHz NMR (DMSO/D2O): 8.41 (s,1), 7.79 (d,1), 7.35 (m,6), 7.10 (m,1), 5.17 (s,2), 4.90 (d,1), 4.76 (d,1), 4.08 (d,1), 2.25 (m,1), 0.90 (d,3), 0.75 (d,3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.[I:12]I>CO.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([I:12])[CH2:5][CH2:6][O:7]2
Reactant: Clc1cccc2c1CCCO2
Reactant: II
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: Clc1cccc2c1C(I)CCO2
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of 5-chlorochroman (0.101 g; 0.6 mmol) and silver nitrate (0.112 g; 0.66 mmol) in methanol (6 mL) was added iodine (0.153 g; 0.6 mmol) and the reaction mixture for 30 min. The reaction was quenched by adding a solution of sodium thiosulphate 0.5M (2.5 mL) and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-80%) in heptane furnished 0.088 g (50%) of 5-chloro-4-iodochroman.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[NH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[NH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: N#CC(=C1Nc2ccc(C(=O)O)cc2N1)c1nccc(C(F)(F)F)n1
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2N1)c1nccc(C(F)(F)F)n1
Temperature: 50 °C
Yield: 68 %

Procedure:
The 2-[5-carboxy-1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (450 mg, 1.29 mmol) from the previous step, dissolved in concentrated sulfuric acid (2 mL), was heated to 50° C. for 6 hr. The mixture was cooled to room temperature and added dropwise to rapidly stirred room-temperature water (500 mL). The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to give 2-[5-carboxy-1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (322 mg, 0.88 mmol, 68% yield) as a dark brown solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:34]=[C:35]([C:42]([N:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])=[O:43])[CH:36]=[C:37]([CH:41]=1)[C:38](O)=[O:39].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:2]([NH:1][C:38](=[O:39])[C:37]1[CH:41]=[C:33]([CH3:32])[CH:34]=[C:35]([C:42]([N:44]([CH2:45][CH2:46][CH3:47])[CH2:48][CH2:49][CH3:50])=[O:43])[CH:36]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 6) is dissolved in anhydrous DMF (3 mL) and cooled to 0°. Triethylamine (500 μL, 3.6 mmol) and 5-methyl-N, N-dipropylisophthalamic acid (IX, 156 mg, 0.59 mmol) are added with stirring. The mixture is warmed to 20-25° briefly to allow for complete dissolution of the carboxylic acid, before recooling to 00. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) is added with stirring, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2 mmol). The resulting mixture is stirred at 0° for 5 min, then warmed to 20-25° for 15 hr. The mixture is then quenched with aqueous citric acid (10%), and the mixture extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate, saline, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (2-10% methanol/methylene chloride gradient elution) to give purified title compound, MS (ES) MH+=582.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:15]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)nc1
Yield: 100 %

Procedure:
6-Aminonicotinic acid (1.06 g, 7.7 mmol) was suspended with stirring in anhydrous methanol (50 ml), and thionyl chloride (0.55 ml, 7.7 mmol) was added dropwise. The suspension was refluxed to a clear solution over 15 hours. The solvent was evaporated in vacuo and the residue taken up in water (20 ml). The solution was raised to pH 9 (sat. Na2CO3), extracted with chloroform, and dried over MgSO4. Evaporation of the chloroform gave 1.23 g (100%) product as white
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:17]([CH2:20][CH3:21])(=[O:18])=[O:19])[CH3:23])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1oc2cccc(NS(=O)(=O)CC)c2c1C
Product: CCOC(=O)c1oc2cccc(N(C)S(=O)(=O)CC)c2c1C

Procedure:
4-Ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (prepared according to Example 68, Step 1) was alkylated with iodomethane according to Example 60, Step 2, to give 4-(ethanesulfonyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (m, 9 H) 2.7 (s, 3 H) 3.3 (s, 2 H) 4.4 (q, J=7.1 Hz, 2 H) 7.5 (dd, J=7.7, 0.9 Hz, 1 H) 7.6 (m, 1 H) 7.7 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ncccc32)n1
Yield: 44.8 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 0.100 g (0.359 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 17.2 mg (0.431 mmol, 60% dispersion in oil) of sodium hydride, 80.2 mg (0.431 mmol) of 2-methyl-6-bromomethyl-pyridine and 3.5 mL of N,N dimethylformamide. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 61.7 mg of 3-(3,4-Dimethyl-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H21N3O2 [M+H]: 384.2 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([O:27]CC#C)=[O:26].[OH-].[Na+].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([OH:27])=[O:26]
Reactant: C#CCOC(=O)[C@H]1CN(CC#C)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 17 h
Yield: 69.5 %

Procedure:
0.3 g of (prop-2-ynyl) (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 3 cm3 of dioxane and 1.48 cm3 of N sodium hydroxide were heated, with stirring, at a temperature in the region of 70° C. for 17 hours. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 1.48 cm3 of normal aqueous hydrochloric acid were added to the solid residue obtained, followed by 10 cm3 of water. The solution obtained was extracted with 5 times 20 cm3 of dichloromethane. The organic extracts were combined and then concentrated under reduced pressure (5 kPa). 0.189 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylic acid was obtained in the form of a foam with a white color.
Reaction SMILES: [NH2:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C([O-])([O-])=O.[K+].[K+]>>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][NH:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23][S:15]([CH3:16])(=[O:32])=[O:31])=[CH:22][C:16]=3[S:15](=[O:31])(=[O:32])[N:14]=2)[C:3]1=[O:33])[CH3:45]
Reactant: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CNC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
Follow same procedure as Example 18D, treating the product of Example 18C with ethyl bromoacetate (5.7μL, 0.05 mmol) and K2CO3 (6.8 mg, 0.05 mmol). 1H NMR (d6-DMSO) δ 13.81 (s, 1H), 9.98 (s, 1H), 8.16, 8.13 (d, 1H), 7.85, 7.83 (d, 1H), 7.69-7.43 (m, 4H), 7.38, 7.35 (d, 1H), 4.15-4.00 (q, 2H), 3.44, 3.38, 3.23, 3.17 (dd, 1H), 3.02 (s, 3H), 2.32-2.16 (m, 1H), 2.15-2.01 (m, 1H), 1.38-1.21 (m, 2H) 1.21-1.09 (t, 3H), 1.09-0.93 (m, 1H), 0.73-0.62 (q, 6H), 0.55-0.42 (m, 1H); MS (ESI) m/z 605 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:12]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CC(C)OC(=O)c1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(-c2ccc(C(C)(C)O)nc2)ccn1
Temperature: 85 °C
Yield: 46.6 %

Procedure:
A mixture of crude 2-(isopropoxycarbonyl)pyridin-4-ylboronic acid (700 mg, ˜1.0 mmol), dppf(Pd)Cl2 (40 mg, 5 mol %), potassium carbonate (280 mg, 2.0 mmol) and 2-(5-bromopyridin-2-yl)propan-2-ol (216 mg, 1.0 mmol) in degassed toluene (3 mL), degassed water (1 mL) and degassed isopropanol (1 mL) was heated at 85° C. for 1 hour. The aqueous layer was discarded and the solvent removed under reduced pressure. The residue was purified by flash chromatography (rf: 0.53 in 20:1 ethyl acetate:methanol) to give isopropyl 6-(2-hydroxypropan-2-yl)-3,4′-bipyridine-2′-carboxylate (140 mg, 47% yield). 301.1 (M+1).