Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18]([O:22][CH3:23])([O:20][CH3:21])[CH2:17][CH2:16][NH:15]2)=[C:10]([CH3:24])[CH:9]=1>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][C:18]([O:22][CH3:23])([O:20][CH3:21])[CH2:17][CH2:16][NH:15]2)=[C:10]([CH3:24])[CH:9]=1
Reactant: COC1(OC)CCNC(c2ccc(F)cc2C)C1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC1(OC)CCN[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 29.1 %

Procedure:
To 130 ml of ethyl acetate suspension of 10.1 g of 2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3.18 g of L-N-acetylvaline was added 35 ml of methanol, and the mixture was heated to dissolve, and then, cooled down at room temperature. After 3.5 hours, precipitated crystals were collected by filtration, and washed with 20 ml of ethyl acetate. The obtained crystals were dried under reduced pressure. Subsequently, 50 ml of chloroform was added thereto, and the mixture was washed with 30 ml of a 2M aqueous sodium hydroxide solution and 30 ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the obtained residue was added ether, and precipitated crystals were further concentrated under reduced pressure, to give 2.94 g of (2R)-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine (optical purity:97.0% ee) as shown in Table 125 below.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[C:17]3[CH:23]=[N:22][N:21](CC4C=CC(OC)=CC=4)[C:18]3=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1.C(Cl)[Cl:47]>>[ClH:47].[ClH:47].[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:17]3[CH:23]=[N:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4cccc(F)c4)cnc32)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Fc1cccc(-c2cnc3[nH]ncc3c2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
TFA (1 mL) was added to tert-butyl 4-(5-(3-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.25 g, 0.483 mmol) in DCM (5 mL) and stirred at room temperature for 2 hours. The reaction was then concentrated to dryness and dried under vacuum for 3 hours. TFA (1.86 mL, 24.2 mmol) was then added, and the mixture was heated to 65° C. for 3 hours. The reaction was then concentrated to dryness. The resulting residue was dissolved in DCM (2 mL), and HCl in ether (2 mL, 2M) and ether (5 mL) were added. The resulting solid was collected by filtration to give 5-(3-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.17 g, 94%). MS ESI (+) m/z 298.1 detected.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CS[C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13](=[O:14])[N:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=[C:22]23)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CSc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c2nc3ccccc3n12
Yield: 62 %

Procedure:
the following compound was prepared from 2-(3-nitrophenylamino)-benzoyl chloride and 2-methylthiobenzimidazole: 5-(3-nitrophenyl)-benzimidazo-[2,1-b]-quinazolin-12(5H)-one ##STR14## Yield: 62% of theory, melting point 294° C.; N calculated 15.72%; N found 15.73%.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[Cl:17].O[Li].O>O.O1CCOCC1>[Cl:17][C:5]1[N:6]=[C:7]([CH3:16])[CH:8]=[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]=1[C:3]([OH:18])=[O:2]
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)OC
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)O

Procedure:
The title compound was prepared by reaction of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl ester with LiOH.H2O in a mixture of water and dioxane at room temperature. The desired product was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The title compound was obtained as white crystals after titration with ethyl acetate. mp. 164–165° C.; anal. For C12H17Cl2O2 cacl. C, 56.14; H, 6.67; N, 10.91; found: C, 56.40; H, 6.53; H, 10.93.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:21])=[O:10])=[N:6][CH:7]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(O)c1ncc(Br)cc1Cl
Agent: Cl
Product: O=C(Nc1ccc(O)cc1O)c1ncc(Br)cc1Cl

Procedure:
Using 5-bromo-3-chloropyridine-2-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[C:11]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)N)#[N:12]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[OH:10][C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:3]=1[N:1]([C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=1[OH:10])[C:18]1[CH:19]=[C:13]([CH:14]=[CH:15][CH:17]=1)[C:11]#[N:12]
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Reactant: N#Cc1cccc(N)c1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: N#Cc1cccc(N(C2=C(O)CCCC2=O)C2=C(O)CCCC2=O)c1
Temperature: 80 °C

Procedure:
2-Diazo-cyclohexane-1,3-dione (2 mmoL), prepared by the literature known procedure, 3-cyano-aniline (1 mmoL) and rhodium acetate dimmer (0.01 mmoL) in benzene (10 mL) were heated at 80° C. for 4˜6 hrs. The solid was filtered off and the filtrate was concentrated to give a yellow oil, which was purified by silica gel chromatography to afford the title compound as a white solid.
Reaction SMILES: ClC(OC(Cl)C)=O.[O:8]([CH2:15][C:16]1[S:17][C:18]2[CH2:19][N:20](CC3C=CC=CC=3)[CH2:21][CH2:22][CH2:23][C:24]=2[N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:8]([CH2:15][C:16]1[S:17][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]=2[N:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(OCc2nc3c(s2)CNCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
1-Chloroethyl chloroformate (0.034 mL, 0.31 mmol) was added to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepine (0.055 mg, 0.16 mmol) and DIPEA (0.08 mL, 0.47 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. Then, the solvent was evaporated in vacuo and a solution of the crude product in MeOH (1 mL) was stirred at 70° C. for 1 hour. The mixture was treated with a 7M solution of ammonia in MeOH and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 3 /97). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepine (0.033 g, 81% yield) as a yellow oil. C14H16N2OS LCMS: Rt 1.13, m/z 302 [M+ACN+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20]>C(#N)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)[C@H](CO)Nc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 10.05 g (36.6 mmol) of 2,4-Dichloro-5-iodo-pyrimidine and 5.6 ml (40.0 mmol) triethylamine in 30 ml of acetonitrile is mixed with 4.85 g (47.0 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally diluted with water. The batch is filtered and the solid is washed with small amounts of acetonitrile and water. The solid is dried. 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=O)([O-])=O.CI.[C:21](OCC)(=O)C.C[N:28](C)[CH:29]=[O:30]>>[CH3:21][N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:9][C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([NH:3][C:29]([NH2:28])=[O:30])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
50% Sodium hydride 2.15 g (89 mmol) was suspended, under nitrogen atmosphere, in 100 ml of anhydrous dimethylformamide. A solution of 10 g (46 mmol) of 2-(3'-nitrobenzoyl)pyrrole in 50 ml of anhydrous dimethylformamide was added thereto, and the resulting mixture stirred for 1 hour, cooled to 0° C. and then treated dropwise with a solution of 8.6 ml (130 mmol) of methyl iodide in 30 ml of dry dimethylformamide. The reaction mixture was stirred for an additional hour at 0° C. and thereafter poured into 500 ml of ethyl acetate, the extract was washed with water (5×250 ml), dried and evaporated in vacuo. The residue was crystallized from methylene chloride-hexane, to produce 9.6 g (90%) of the title compound, 1-methyl-2-(3'-nitrobenzoyl)pyrrole. M.P. 115°-117° C. (methylene chloride-methanol)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[Cl:13][CH2:14][CH2:15][NH2:16].[Cl:17][CH2:18][CH2:19]N.C(N(CC)CC)C>ClCCl.O1CCCC1>[Cl:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:18][Cl:17])[C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCCl)CCCl
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a solution, cooled to 0° C., of 15 g (84 mmol) of bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran, stirred beforehand for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 20 g of crude residue are obtained and purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 6 g (26%) of benzyl bis(2-chloroethyl)carbamate are thus obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]([NH:15][NH2:16])=O)=[C:10]([F:17])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:15]([C:13]([CH2:12][C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:17])[N:7]=[CH:6][CH:5]=[CH:4]4)=[N:20][N:21]=2)[N:16]=1
Reactant: NNC(=O)Cc1c(F)cc2ncccc2c1F
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Yield: 58.8 %

Procedure:
A solution of (5,7-difluoro-quinolin-6-yl)-acetic acid hydrazide (1.024 g, 4.32 mmol) and 3,6-dichloropyridazine (0.772 g, 5.18 mmol) in 60 mL of butan-1-ol was heated at 135° C. in a sealed tube for 16 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford 842 mg of the title compound as a gray solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (dd, 1H), 8.26 (d, 1H), 7.60-7.66 (m, 2H), 7.45 (d, 1H), 4.81 (s, 2H). LCMS (method A): [MH]+=332, tR=4.88 min.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:4]1[CH2:19][CH2:20][N:21]=[N+:22]=[N-:23].C1(O)CCCCC1.[OH-].[Na+].Cl[C:34]1[N:39]=[C:38]([N:40]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([Cl:47])[N:35]=1>>[N:40]1([C:38]2[CH:37]=[C:36]([Cl:47])[N:35]=[C:34]([NH:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:10])[CH:4]3[CH2:19][CH2:20][N:21]=[N+:22]=[N-:23])[N:39]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: [N-]=[N+]=NCCC1C(N)CCCN1C(=O)OCc1ccccc1
Reactant: Clc1cc(N2CCCCCC2)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OC1CCCCC1
Product: [N-]=[N+]=NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Yield: 40.9 %

Procedure:
The compound 16 (118 mg), cyclohexanol (0.16 mL), aqueous 5N sodium hydroxide solution (0.25 mL) and 1-(2,6-dichloropyrimidin-4-yl)azepan (83.5 mg) were stirred at 120° C. for 6 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to obtain the title compound (71.2 mg) having the following physical properties.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:4][CH:3]=2)=[CH:25]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccoc3)n3cnnc23)CC1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (800 mg, 2.08 mmol), furan-3-ylboronic acid (349 mg, 3.12 mmol), Pd(PPh3)4 (240 mg, 0.312 mmol), Cs2CO3 (1.00 g, 3.12 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.75 g (97%) of the product as a yellow solid. MS m/z: 371 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]([NH:22][NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=O)=O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:39][C:24]([CH:26]5[CH2:28][CH2:27]5)=[N:23][N:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1
Reactant: COC(=O)c1nc2n(c1C(=O)NNC(=O)C1CC1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 25 °C

Procedure:
Methyl 10-bromo-3-(2-(cyclopropanecarbonyl)hydrazinecarbonyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was dissolved in toluene (0.56 mL) and treated with Lawesson's reagent (1.3 equiv., 29.8 mg, 0.07359 mmol). The reaction was heated to reflux until judged complete by LC/MS analysis. The solution was cooled to room temperature. Water was added and the solution was extracted 2× with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated in vacuo. The crude material was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].C=O.[C:32]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][N:26]([CH3:32])[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCN(C)CC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
5-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(piperidin-4-yl)amino)benzamide (0.08 g, 0.192 mmol) was dissolved in methanol (5 mL) and cooled to 0° C., formalin (0.028 g, 0.965 mmol) was added. Resulting reaction mass was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.023 g, 0.38 mmol) was added to above reaction mass and stirred at room temperature for 4 h. After completion, solvent were removed under reduced pressure and water was added to the residue, extraction was carried out using DCM. Combined organic layers were dried, concentrated and purified by column chromatography giving the desired compound (0.02 g, 24%): LCMS: 431.25 (M+1)+; HPLC: 98.80% (@ 254 nm) (Rt; 4.757; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.20 (t, 1H), 7.15 (d, 1H, J=1.2 Hz), 6.94 (d, 1H, J=2 Hz), 5.85 (s, 1H), 4.25 (d, 2H, J=4.8 Hz), 3.05 (bs, 2H), 2.88 (bs, 1H), 2.55 (s, 3H), 2.44 (bs, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.68 (bs, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Reactant: C#CC1CC1
Product: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]

Procedure:
5-Bromo-3-nitrothiophene-2-carboxylic acid methyl ester was reacted with ethynylcyclopropane by method Q. The product with the molecular weight of 251.26 (C11H9NO4S) was obtained in this way; MS (ESI): 252 (M+H+).
Reaction SMILES: [CH2:1]([NH:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](Cl)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].[OH-].[Na+]>>[CH2:1]([N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)CCCCCCCl
Reactant: CCCCCCCCCCNC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCN(C)CCCCCCC(C)C
Temperature: 190 °C
Yield: 83 %

Procedure:
A mixture of 300 moles of decylmethylamine, 300 moles of isononyl chloride and 350 moles of 50% caustic soda, contained in a 50 gallon reactor, was heated for 6 hours at a temperature of 190° C. The organic mixture was cooled, washed with water and further purified by fractional distillation. The amination process afforded a yield of 83% decylisononylmethylamine. When nonyl chloride is used instead of isononyl chloride, the product is decylnonylmethylamine.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH2:9])=O)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[S:19])[NH2:9])[CH:3]=1
Reactant: Cc1cc(C(N)=O)no1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(N)=S)no1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
A suspension of 525 mg (4.16 mmol) of 5-methylisoxazole-3-carboxamide and 1.85 g (4.58 mmol, 1.1 equiv) of Lawesson's reagent in 15 mL of dry toluene was heated to reflux for 5 h, during which time the reaction mixture became a clear yellow color. The reaction mixture was cooled to RT and the solvent was removed in vacuo. Purification of the material by silica gel flash column chromatography using a gradient of hexane/EtOAc 5/1 to hexane/EtOAc 1/1 as eluent followed by trituration with acetonitrile, filtration to remove the solid Lawesson's reagent byproducts and removal of solvent afforded 614 mg of the title compound as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 8.05 (s, br, 2H), 6.52 (s, 1H), 2.46 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1.C([C:15]([OH:19])([OH:18])CC)C.[CH3:20][C:21]1[CH:22]=[CH:23][C:24](S(O)(=O)=O)=C[CH:26]=1>C1(C)C=CC=CC=1>[F:12][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:10][C:11]=1[CH:15]1[O:19][CH2:26][CH:21]([CH2:22][CH2:23][CH3:24])[CH2:20][O:18]1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(O)(O)CC
Solvent: Cc1ccccc1
Product: CCCC1COC(c2ccccc2OC(F)F)OC1

Procedure:
17.2 g of p-difluoromethoxybenzaldehyde (commercially available from Fluorochem. Ltd. (GB)), 10.4 g of ethylpropanediol and 0.2 g of p-TsOH are heated to boiling for 2 hours in 100 ml of toluene. After evaporation of the solvent, the mixture is worked up as usual.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1)(=[NH:25])[NH2:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=N)N)cn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cnc(C(=N)N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
[6-(5-Carbamimidoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (77 mg, 0.21 mmol) was dissolved in THF (3 mL) and methanol (1.2 mL). To this was added lithium hydroxide monohydrate (70 mg, 1.7 mmol) in water (1.2 mL) at 0° C. The reaction was warmed up to room temperature and stirred for 4 h. The reaction mixture was acidified to pH 3 with aqueous HCl (6 N). The solvent was removed. Prep-HPLC separation (C18 column) of the reaction mixture gave the title compound (35 mg, 49%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (1H, s), 8.20 (1H, s), 6.85 (1H, s), 6.65 (1H, s), 5.18 (1H, dd), 2.64 (1H, dd), 2.16 (3H, s), 2.15 (1H, m). MS found (electrospray): (M+H)+=343.2.
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[CH2:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][CH2:8][CH2:7]1>O>[N:2]([N:9]1[CH2:8][CH2:7][CH2:6][CH2:11][CH:10]1[C:12]([OH:14])=[O:13])=[O:4]
Reactant: O=C(O)C1CCCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCCC1C(=O)O
Reaction time: 1 h

Procedure:
Conc. HCl (1.96 mL) and NaNO2 (2.2 g) were added to the H2O (21 mL) solution of DL-pipecolic acid (3.04 g) under a nitrogen atmosphere at 0° C. and stirred for 1 h. The solution was extracted with CH2Cl2 and organic layer was washed with brine. The mixture was dried over Na2SO4 and concentrated under reduced pressure to afford crude (2RS)-1-nitrosopiperidine-2-carboxylic acid as pale yellow crystals.