Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([NH2:12])[CH3:11]
Reactant: C[C@@H](Cc1cc(F)ccc1Br)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N)Cc1cc(F)ccc1Br
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To a solution of (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethyl azide (1.00 g, 3.87 mmol) in 20 mL of THF and 4 mL of water was added PPh3 (2.03 g, 7.74 mmol) and the mixture was stirred for 4 h. The solvent was evaporated and the residue was purified by silicagel column eluting first with DCM, then DCM:MeOH:NH4OH (94:5:1). The fraction with product was evaporated to give (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine (134 mg, 15%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 1H), 6.97 (m, 1H), 6.83 (m, 1H), 3.28 (m, 1H), 2.66-2.87 (m, 2H), 1.68 (s, 2H), 1.17 (d, J=6.21 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(COCCCCBr)cc1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccc(COCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,4-dimethoxybenzyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,4-dimethoxybenzyloxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(S[CH2:5][C@H:6]1[C@@H:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7]1)(C)C.O[O:28][S:29]([O-:31])=O.[K+].[CH3:33][CH:34](O)[CH3:35]>O>[CH:34]([S:29]([CH2:5][C@H:6]1[C@@H:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7]1)(=[O:31])=[O:28])([CH3:35])[CH3:33]
Reactant: CC(C)O
Reactant: CC(C)SC[C@@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC(C)S(=O)(=O)C[C@@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl ((7R,8S)-7-(isopropylthiomethyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate (2.72 g, 7.16 mmol) in i-PrOH (60 ml) was treated with a solution of Oxone® (8.8 g, 14 mmol) in water (30 ml) and stirred at room temperature for 1 hour. The mixture is diluted with water and extracted into CH2Cl2. The extracts were washed with water, brine and the solvent removed under vacuum. The residue is chromatographed on silica gel (10-50% Ethyl acetate/hexane) to give 2.3 g of benzyl ((7R,8S)-7-(isopropylsulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2cccc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 6.5 mL of 3-chlorobenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 122°-124° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.96 (dd, 1H), 3.60 (dd, 2H), 5.68 (dd, 1H), 7.25-7.42 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:24]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=C2SC(N3CCN(S(C)(=O)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 52 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (50 mg, 92 μmol) (from Example 23) chloroform (5 mL), methyl sulfonyl chloride (3 equiv, 32 μL) and TEA (3 equiv, 40 μL). The reaction was stirred at 60° C. under N2. The reaction solution was diluted with DCM (70 mL), washed with aq NH4Cl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 90:10) to provide the title compound as a white solid (30 mg, 52%). 1H NMR (DMSO-d6) δ 7.99 (2H, s), 7.94 (1H, s), 7.62 (1H, s), 7.18 (1H, s), 7.13 (1H, dd, J1=2.0 Hz, J2=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 5.37 (2H, s), 4.06 (2H, m), 3.88 (3H, s), 3.74 (2H, m), 3.31-3.36 (4H, m), 2.85 (3H, s); MS (ESI) 624 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:57][C:58]1[CH:59]=[C:60]([N:64]2[CH2:68][CH2:67][CH:66]([C:69](O)=[O:70])[C:65]2=[O:72])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:69]([CH:66]1[CH2:67][CH2:68][N:64]([C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=2)[C:65]1=[O:72])=[O:70]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(F)c2)C1=O
Yield: 41.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.350 g; 0.672 mmol), N,N-diisopropylethylamine (0.232 mL; 1.34 mmol) and 1-(3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (41%) of the title compound as a white solid.
Reaction SMILES: O.[C:2]([NH:4][C:5](=[N:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])SC)#[N:3].[CH3:19][NH2:20]>O>[CH3:19][NH:20][C:5]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])=[N:4][C:2]#[N:3]
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Reactant: CN
Solvent: O
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
N-cyano-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-S-methylisothiourea monohydrate (14.35 g; 0.05 mole) is suspended in distilled water (50 ml), stirred and heated. At a bath temperature of 50° C., aqueous methylamine solution (18.5 ml containing 411 g/liter of methylamine, i.e. 0.245 mole equal to 4.9 equivalents) is added. The evolving gas is led to an equipment for destruction (annihilation). The reaction mixture is kept in a bath of 50°-55° C. for 2.5 hours. Initially, the mixture becomes considerably thinner, then, in most cases, N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidine begins to precipitate without appearing of a complete solution. The mixture becomes thicker and eventually the stirring is stopped. After 2.5 hours the mixture is rapidly heated to 90° C. and stirred at this temperature for 30 minutes. The solution should not contain undissolved material. The solution is poured without cooling onto stirred ice (70 g). A clear solution of 0° to 10° C. is formed which becomes turbid and granular, and well-settling crystals separate. The solution is kept in a refrigerator for 2 hours, then filtered and washed with distilled water (2×10 ml). The wet weight of this precipitate is 14.8 g. After drying at 40° C., the dry weight of N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidine H is 12.27 g (90.82%); m.p. 73°-75° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8](O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[ClH:4].[C:8]([Cl:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalic chloride (800 μL) is added dropwise to a solution of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoic acid, hydrochloride (2.33 g) in dichloromethane (20 mL) containing one drop of N,N-dimethylformamide. The mixture is stirred for two hours at room temperature and concentrated under reduced pressure. Cyclohexane is added and evaporated under reduced pressure to afford 2.55 g of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoyl chloride, hydrochloride used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[CH3:11].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O.P(=O)(O)(O)O>CO>[OH-:12].[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:15]1[C:8]2[C:7]([O+:12]=[C:7]3[C:8]=1[CH:9]=[C:10]([CH3:11])[C:5]([NH:4][CH2:3][C:2]([F:13])([F:14])[F:1])=[CH:6]3)=[CH:6][C:5]([NH:4][CH2:3][C:2]([F:1])([F:14])[F:13])=[C:10]([CH3:11])[CH:9]=2)([OH:20])=[O:19]
Reactant: Cc1ccc(O)cc1NCC(F)(F)F
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: Cc1cc2c(-c3ccccc3C(=O)O)c3cc(C)c(NCC(F)(F)F)cc3[o+]c2cc1NCC(F)(F)F
Product: [OH-]
Yield: 73 %

Procedure:
3-Trifluoroethylamino-4-methylphenol (13.9 g; 0.068 mole) and phthalic anhydride (15.05 g; 0.102 mole-1.5 mole equivalents) were heated in a 500 ml round-bottom, single-neck flask equipped with a short, water-cooled reflux condenser in a 160° oil bath for three hours. A temperature in the range of 150°-180° C. is acceptable. At the start of the reaction the melt was swirled from time to time to facilitate mixing. A further batch of 3-trifluoroethylamino-4-methylphenol (14.0 g; 0.068 mole) was warmed with 85% phosphoric acid (25 ml plus 10 ml) and was transferred to the cooled reaction mixture. The flask was heated for four hours at an oil bath temperature of 170°; again with occasional swirling. Methanol (170 ml; 25 ml per 0.01M) was added to the cooled but still warm reactants and the mixture was refluxed for twenty minutes. Crystals appeared almost immediately and the liquid was stored in a 4° refrigerator overnight. Filtration, washing with cold methanol, and drying gave 25.1 g of red-orange crystals. A second crop 0.9 g (total yield 73%) came from the filtrate kept several days at 4° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[CH:4]\[C:5]([OH:7])=[O:6])/[CH3:3].[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH2:12]>>[C:5]([OH:7])(=[O:6])[CH2:4][C:2]([C:1]([OH:9])=[O:8])([OH:15])[CH3:3].[C:10]([OH:18])(=[O:17])/[C:11](=[CH:13]/[C:14]([OH:16])=[O:15])/[CH3:12]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: C/C(=C/C(=O)O)C(=O)O
Product: C/C(=C\C(=O)O)C(=O)O
Product: CC(O)(CC(=O)O)C(=O)O

Procedure:
isomerizing citraconic acid to itaconic acid in an aqueous solution at a first temperature of about 140° C. to 200° C., which produces citramalic acid and mesaconic acid as by-products;
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][OH:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.C1COCC1>[Si:20]([O:14][CH2:13][C@H:2]([NH2:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CO)Cc1c[nH]c2ccccc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of D-Tryptophanol (1.024 g) and imidazole (403 mg) in DCM (40 ml) and THF (8 ml) was added a solution of tert-butyldimethylsilyl chloride (0.852 g) in DCM (5 ml) dropwise. The reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and the reaction mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with heptane and increasing amounts of ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reactant: CI
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (1.8 g) in N,N-dimethylformamide (15 mL)was treated sequentially with iodomethane (50 mL) and Ag2O (5.52 g), and the mixture was stirred at rt overnight. The mixture was filtered through Celite and the solids were washed with ethyl acetate. The combined filtrates were washed sequentially with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:3 v/v ethyl acetate-hexane, to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(methoxymethyl)cyclohexylcarbamate as a colorless gum (1.78 g). MS found: (M+H)+=393.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1cccc(C(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OCC)(=[O:24])[C:21]([NH2:23])=[O:22]>C(O)C>[CH2:1]([NH:19][C:20]([C:21]([NH2:23])=[O:22])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C(N)=O
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(N)=O
Temperature: 25 °C

Procedure:
13.5 Grams of octadecylamine, 6.4 g of ethyl oxamate and 200 ml of ethanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 1 hour. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and was recrystallized from ethanol to obtain 12.8 g of the desired product. m.p. 169° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:4][C:5]([Cl:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[Cl:12][C:5]1[C:6]2[C:11]([C:2]3[NH:1][S:24](=[O:26])(=[O:25])[N:23]([CH3:22])[CH:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[C:3]=3[CH:4]=1)=[N:10][CH:9]=[CH:8][CH:7]=2
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)cc2)cc(Cl)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2cc(Cl)c3cccnc3c2NS1(=O)=O
Yield: 44.4 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-5-chloro-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 400 (105 mg, 0.34 mmol), N-methylsulfamoyl chloride 213 (135 mg, 1.0 mmol) and NaBH4 (14 mg, 0.34 mmol) in pyridine (4 ml) gave the title compound (57 mg, 44%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:13]=[CH:12]O[C:10](=[O:14])[C:9]=2[CH:15]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:34]([CH2:35][O:36][CH3:37])[N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1.O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[CH:15]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[CH:12][N:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([CH2:35][O:36][CH3:37])[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=1)[C:10]2=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: COCn1nnnc1-c1ccccc1-c1ccc(CN)cc1
Reactant: CCCCc1ccc2ncoc(=O)c2c1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCc1ccc2ncn(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Yield: 43.5 %

Procedure:
A mixture of 6-n-butyl-4H-3,1-benzoxazin-4-one (1.4 g, 6.89 mmol) and 5-(4'-aminomethylbiphenyl-2-yl)-N-methoxymethyltetrazole (2.85 g, ca. 9.65 mmol) in xylene (50 ml) was heated under reflux for 8 hours while water was removed by a Dean-Stark trap. After cooling, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with chloroform-ethyl acetate (1% to 10%) to give 1.44 g (43.6%) of the title compound as a colorless crystal.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C@H:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (R)-2-amino-3,3-dimethylbutanoic acid (43.1 mg, 0.329 mmol) and DCM (2 mL). The reaction mixture were stirred at room temperature in for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H29N3O6, 420; found, 420.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>C(#N)C>[Br:20][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1cc(CO)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(CBr)ccc1F
Temperature: 85 °C
Reaction time: 20 h

Procedure:
(Step 1) Triphenylphosphine (3.21 g) was suspended in acetonitrile (50 ml), bromine (0.64 ml) was added, and the mixture was stirred for 30 min. [4-Fluoro-3-(methylsulfonyl)phenyl]methanol (2.5 g) was added to the reaction mixture, and the mixture was stirred at 85° C. for 20 hr, treated with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:1) to give 4-(bromomethyl)-1-fluoro-2-(methylsulfonyl)benzene (1.64 g).