Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[BrH:6].[CH2:7](O)[CH2:8][CH2:9][OH:10]>>[Br:6][CH:3]([CH3:4])[CH2:2][CH:1]1[O:10][CH2:9][CH2:8][CH2:7][O:5]1
Reactant: OCCCO
Reactant: Br
Reactant: C/C=C/C=O
Product: CC(Br)CC1OCCCO1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 1.4 %

Procedure:
Adapting a procedure of Büchi and Wüest (J. Org. Chem, 1969, 34, 1122–1123), crotonaldehyde (3 g, 43 mmol) was added dropwise to cone. aq. HBr (5.2 g, 64 mmol) over 5 min at 5° C. under air atmosphere. After 15 min of stirring at 5° C. during which time the mixture changed from colourless to brownish, 1,3-propanediol (8.1 g, 107 mmol) was added and the reaction was stirred at 5° C. for further 0.5 h before allowing it warn to rt, and finally stirring it at rt for 2 h. The crude reaction mixture was then n-heptane extracted (2×200 mL), the combined n-heptane extracts were Na2SO4 dried, evaporated in vacuo and 121JP80 was isolated by Kugelrohr distillation (75° C., 0.18 mmHg) to obtain 124 mg (1.4%) of the title compound as a colourless liquid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:19]([CH:22]=4)[CH:20]=[O:21])[O:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.P([O-])(O)(O)=[O:31].[K+].CC(=CC)C.[Cl:41]([O-])=O.[Na+]>CC(O)(C)C.O>[ClH:41].[NH:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[C:19]([CH:22]=4)[C:20]([OH:31])=[O:21])[O:12][N:11]=3)=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: O=P([O-])(O)O
Reactant: CC(Oc1ccc(-c2nc(-c3ccc4nc[nH]c4c3)no2)cc1C=O)C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(Oc1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(=O)O)C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a mixed solution of 5-[3-(1H-benzimidazol-6-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1-methylethoxy)benzaldehyde (83 mg), potassium dihydrogen phosphate (421 mg), and 2-methyl-2-butene (0.5 ml) in tBuOH (2 ml) and water (0.5 ml) was added sodium chlorite (187 mg) at room temperature. The mixed reaction solution was stirred at room temperature for 3 hours, followed by dilution with water (10 ml), and extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. To a solution of the residue in dioxane was added a 4 N HCl-dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain 5-[3-(1H-benzimidazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1-methylethoxy)benzoic acid hydrochloride (80 mg) as white powders.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)O1>>[F:12][CH:11]([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:26]3[CH:25]=[C:24]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:22][CH:27]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: FC(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)F)ccn23)c1
Yield: 58 %

Procedure:
3-Bromo-7-difluoromethylimidazo[1,2-a]pyrimidine (248 mg, 1.00 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-difluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (201 mg, 58%) as a yellow powder: δH (400 MHz, CDCl3) 6.67 (1H, t, J 55) 7.29 (1H, d, J 7), 7.52 (1H, td, J 9 and 1), 7.58-7.74 (5H, m), 7.87 (2H, m), 8.01 (1H, s), 9.12 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH3:20])([CH3:19])[C:17]#N)=[CH:14][CH:13]=1.[OH2:23].Cl>CCCCCC.C(OCC)C>[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH3:20])([CH3:19])[CH:17]=[O:23])=[CH:14][CH:13]=1
Reactant: O
Reactant: CC(C)(C#N)c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0° C. After the addition is complete, water and 6N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30° C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as an oil (31.1 g, 94% yield).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=O.O.NN>C(O)C>[F:1][C:2]([F:47])([F:48])[C:3]1[CH:4]=[CH:5][C:6]2[N:18]3[C:19]([CH2:35][NH2:36])=[N:20][N:21]=[C:22]3[CH2:23][N:24]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]=2[CH:17]=1
Reactant: O=C(c1ccccc1Cl)c1cc(C(F)(F)F)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-trifluoromethyl-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-trifluoromethyl-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][N:5]=[C:6]([C:26](=[N:28][O:29][CH3:30])[CH3:27])[C:7](=[N:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][N:20]=[CH:21][C:22]([O:24]C)=O)[CH3:8]>O1CCCC1>[CH3:1][NH:2][C:22](=[O:24])[CH:21]=[N:20][O:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][N:9]=[C:7]([CH3:8])[C:6](=[N:5][O:4][CH3:3])[C:26](=[N:28][O:29][CH3:30])[CH3:27]
Reactant: CON=C(C)C(=NOC)C(C)=NOCc1ccccc1CON=CC(=O)OC
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C=NOCc1ccccc1CON=C(C)C(=NOC)C(C)=NOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2 ml of 40% strength aqueous methylamine solution are added to a solution of 0.6 g (1.5 mmol) of methyl [2-(2,3-bismethoxyimino-1-methylbutylideneaminooxymethyl)phenyl]methoxyiminoacetate in 10 ml of tetrahydrofuran, and the mixture is stirred for 12 hours at room temperature. For working up, the reaction mixture is evaporated in vacuo, taken up in 20 ml of diethyl ether, washed using 20 ml of water, dried over sodium sulfate and evaporated in vacuo. This gives 0.6 g (98%) of an oil.
Reaction SMILES: Cl.C([O:4][C:5](=[O:33])[CH:6]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[NH:32])[NH2:31])=[CH:26][CH:25]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:9]([O:16][C@@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:8]=1[F:22])C.[Li+].[OH-].Cl>C1COCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][CH:6]([C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:9]([O:16][C@@H:17]3[CH2:21][CH2:20][O:19][CH2:18]3)[C:8]=2[F:22])[C:5]([OH:33])=[O:4])=[CH:25][CH:26]=1)(=[NH:31])[NH2:32]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(O[C@@H]2CCOC2)c(F)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A suspension of 170 mg (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester hydrochloride described in example 3.8 in 5 ml THF was cooled to 0° C. and treated with 1.8 ml 1N LiOH solution. The mixture was stirred for 2 hrs at 0° C., then neutralized with 1N HCl. The precipitate was filtered off and washed with H2O and Et2O to yield 129 mg of (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid as an off-white solid. This isomeric mixture was separated into the diastereomers by preparative HPLC on a chiral stationary phase (Chiralpak AD) using heptane/isopropanol/trifluoroacetic acid (75:25:0.2) as a mobile phase to give, after neutralization, (R)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid and (S)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid as off-white solids.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]I)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>CN(C=O)C>[C:36]1(=[O:46])[N:40]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C@H:18]2[CH2:19][CH2:20][C@@:21]3([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]4[C@@H:23]3[CH2:24][CH2:25][C@@:26]3([CH3:27])[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:17]2)[C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCN5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A mixture of 6-(5-cholesten-3β-yloxy)hexyl iodide (1.0 g) and potassium phthalimide (1.0 g) in DMF (25 ml) is heated with stirring for 0.5 hours at 85°-90° C. (bath temperature). The mixture is filtered and the filtrate is evaporated in vacuo to a residue that is partitioned between chloroform and water. The organic layer is washed with aqueous sodium thiosulfate and water, dried, and evaporated to a syrup that crystallizes upon standing. Recrystallization from petroleum ether gives the title compound (0.92 g, 89%) mp 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH2:15]([NH:18][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])=[CH:9][C:2]=1[OH:1])[CH2:16][CH3:17]
Reactant: O=Cc1ccc(C(Cl)=C(Cl)Cl)cc1O
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCNCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.211 g (0.84 mmol) of the product of Step A and 0.177 g (2.94 mmol) of n-propylamine dissolved in 8 mL of CH2Cl2 was added 0.5 g of finely powdered 4 Å molecular sieves. The reaction mixture was stirred under a nitrogen atmosphere at room temperature overnight, then 0.445 g (2.1 mmol) of sodium triacetoxyborohydride was added. The reaction was then stirred an addition 8 h at room temperature, then diluted with CH2Cl2 and MeOH. The mixture was filtered through a pad of Celite filter aid eluted with CH2Cl2, and the filtrate was washed with saturated aqueous NaHCO3. The organic layer was the separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted first with CH2Cl2-MeOH—NH4OH (96:3:1) followed by CH2Cl2-MeOH—NH4OH (94:5:1). Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:15][CH:16]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1)[CH3:24]>CCOC(C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:15][CH:16]=2)=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC(=O)NCCc1ccc(Br)cn1
Reactant: C#Cc1ccc(OCC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#Cc2ccc(CCNC(C)=O)nc2)cc1
Temperature: 80 °C

Procedure:
0.55 mL (3.91 mmol) DIPEA is added to 190 mg (0.78 mmol) N-[2-(5-bromo-pyridin-2-yl)-ethyl]-acetamide (I48.1), 3.72 mg (0.02 mmol) CuI and 13.7 mg (0.02 mmol) bis(triphenylphosphin)palladium-(II)-chloride. 171 mg (1.17 mmol) 4-ethoxyphenylacetylene are added and the reaction mixture is heated for 10 min at 80° C. in a microwave oven. The mixture is diluted with EtOAc and washed with water (1×) and diluted aq. ammonia solution. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:43])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[N:21][CH:20]=3)[CH:14]=2)[C:8]1=[O:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.C(=O)([O-])O.[Na+].ClCCl>CO>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:23][CH:22]=[N:21][CH:20]=3)[CH:14]=2)[CH3:43])[C:8]1=[O:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnc[nH]2)c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-[3-(1-triphenylmethyl-1H-imidazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 74, 55 mg, 0.95 nmmol) in methanol (1.5 ml) was added aqueous hydrochloric acid (2M, 0.5 ml) and the mixture was heated under reflux for 16 h. The reaction mixture was then cooled to room temperature and poured onto solid sodium hydrogen carbonate. Dichloromethane was added, the layers were separated and the organic extracts were dried (MgSO4) and concentrated in in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a clear oil (21 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18]([OH:19])=[N:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.Cl>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][S:31]([CH3:30])(=[O:33])=[O:32])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1nc2nccnc2c(O)c1-c1ncc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 7-(3,5-dichloro-pyrid-2-yl)-pyrido[2,3-b]pyrazine-6,8-diol (Example 1.2) (0.20 g) and N-ethyl-diisopropylamine (0.126 g) in dry dichloromethane (15 ml) was added methane sulfonyl chloride (0.074 g). The reaction mixture was stirred at ambient temperature for one hour and then stored at ambient temperature for 16 hours. The reaction mixture was diluted with aqueous hydrochloric acid (1M). The phases were separated and the organic layer was concentrated. The residue was purified by reverse phase HPLC to give Compound No. A4 of Table A as a pale brown solid (0.055 g).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:15]=[C:14]([O:16][CH3:17])[C:7]2[NH:8]C(=O)[O:10][CH:11]([CH3:12])[C:6]=2[C:5]=1[CH3:18]>CO>[NH2:8][C:7]1[C:14]([O:16][CH3:17])=[CH:15][C:4]([Cl:3])=[C:5]([CH3:18])[C:6]=1[CH:11]([OH:10])[CH3:12]
Reactant: COc1cc(Cl)c(C)c2c1NC(=O)OC2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cl)c(C)c(C(C)O)c1N
Yield: 87.9 %

Procedure:
1N aqueous potassium hydroxide solution (13.5 ml, 13.5 mmol) was added to 6-chloro-8-methoxy-4,5-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.66 g, 2.7 mmol) dissolved in methanol (13.5 ml). The reaction was heated 6 hours to reflux. A solid precipitated. After cooling the reaction was diluted with water, and the title compound was filtered off, washed with water and dried to yield an off-white solid (512 mg, 88%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][I:12])[N:5]=[C:4]([C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[N:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[CH2:24][N:25]=[N+:26]=[N-:27]>>[F:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[N:27]=[N:26][N:25]([CH2:24][C:23]3[CH:28]=[CH:29][CH:30]=[C:21]([C:20]([F:19])([F:32])[F:31])[CH:22]=3)[C:11]=2[I:12])[N:5]=[C:4]([C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cn1cccc1-c1nc(F)nc(OCC#CI)n1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: Cn1cccc1-c1nc(F)nc(OCc2nnn(Cc3cccc(C(F)(F)F)c3)c2I)n1

Procedure:
Synthesized from 2-fluoro-4-(3-iodoprop-2-ynyloxy)-6-(1-methyl-1H-pyrrol-2-yl)-1,3,5-triazine and 3-trifluoromethyl-benzylazide using general procedure; 0.311 g, 0.556 mmol, 80%; mp=185-187° C. (dec.); IR (υ[cm−1]) 3130, 3059, 1595, 1555, 1418, 1357, 1173, 1104, 1056, 911, 803, 756; 1H NMR (600 MHz, CDCl3) δ=7.61-7.58 (m, 2H), 7.50-7.41 (m, 3H), 6.90 (s, 1H), 6.21 (dd, J=3.9, 2.5, 1H), 5.64 (s, 2H), 5.56 (s, 2H), 4.09 (s, 3H); 13C NMR (151 MHz, CDCl3) δ=171.5 (dd, J=361.1, 15.4), 171.3, 169.8, 135.0, 133.0, 131.6 (q, J=32.8), 131.5, 129.9, 125.9 (q, J=3.6), 125.1 (q, J=3.7), 123.9 (q, J=272.4), 121.5, 81.6, 61.7, 54.0, 39.0; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C18H15F4IN7O, 560.0313; found 560.0311.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (from Albany Molecular, 1.5 g, 6.5 mmol) in methylene chloride (20 mL) was treated with pyridine (2.14 mL, 26.5 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (1.01 mL, 13.1 mmol) was added dropwise over 5 min. The reaction was stirred at room temperature for 5 h. The resulting mixture was then concentrated and partitioned between EtOAc and water. The organic phases were concentrated and purified on silica gel (eluting with 50% EtOAc in hexanes) to give the desired product (1.48 g, 74%). LCMS calculated for C13H25NO5SNa (M+Na)+: m/z=330.2. Found: 330.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][C:3]1=[O:29].Cl.O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH2:34]([C:33]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:29])[CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:32]=1)[CH3:35]
Reactant: CN1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1=O
Reactant: CCC(N)=NO
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCN(C)C(=O)C3)C2)n1

Procedure:
250 mg (0.605 mmol) of 1-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 209A) and 82.9 mg (0.665 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 110 mg (39% of theory).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[Cl:7][CH2:8][C:9](Cl)=[O:10]>C(OCC)(=O)C>[Cl:7][CH2:8][C:9]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:10]
Reactant: CNCC(=O)O
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: CN(CC(=O)O)C(=O)CCl

Procedure:
8.8 Grams (0.1 mole) of sarcosine was suspended in 100 ml of ethyl acetate and refluxed under anhydrous conditions with 22.6 grams (0.2 mole) of chloroacetyl chloride for 12 hours. The unreacted sarcosine was then filtered and the excess solvent and chloroacetyl chloride removed from the filtrate by vacuum distillation. The resulting oil was crystallized with the aid of a small quantity of diethyl ether. There was obtained 12.5g (76%) of N-(Chloroacetyl)sarosine whose structure was consistent with infrared analysis and element analysis for C, H, N, and Cl.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[CH3:1][N:2]1[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[NH:9][C:10]1=[O:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cnccc1N
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of 2.80 g (22.7 mmol) of N3-methylpyridine-3,4-diamine in 125 mL of THF was added 4.42 g (27.3 mmol) of 1,1′-carbonyldiimidazole and the reaction was stirred overnight at room temperature. The reaction slurry was concentrated in vacuo to a volume of about 65 mL and cooled in a −10° C. bath, filtered, and the solids washed with 25 mL of THF. The solids were dried under high vacuum to give 2.35 g (69%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:32]([C:27]2[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34; 379 mg, 1.44 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 290 mg, 1.44 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (34 mg, 0.250 mmol) (294 mg, 2.16 mmol), EDC (415 mg, 2.16 mmol) and triethylamine (0.604 ml, 4.32 mmol) in DCM (1 ml) was stirred at room temperature for 16 hours. The reaction was added partitioned between DCM and as saturated solution of sodium bicarbonate. The organics were filtered through a hydrophobic frit and loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile) to afford the title compound.