Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][O:30][C:31]([C:33]1[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=1[NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:32]>CN(C)C=O>[CH3:29][O:30][C:31]([C:33]1[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=1[NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:40][CH2:39]1)=[O:32]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
3.3 Grams of 3,4-dimethoxybenzoic acid was dissolved in 30 ml of dimethylformamide, then 2.4 g of triethylamine was added to this solution. Under ice-cooled condition, to this solution was added dropwise 2.75 g of isobutyl chloroformate with stirring, and further stirred for 30 minutes. Then to this reaction mixture was added dropwise a DMF solution containing 5.8 g of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide and stirred for 5 hours. The reaction mixture was concentrated to dryness and subjected to extraction by adding chloroform and 1 N-sodium hydroxide. The chloroform layer was washed with water, dried and removed by distillation, the residue obtained was crystallized by adding ethyl acetate and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 2.3 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32](=[O:37])[NH:33][NH:34]2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([C:32](=[O:37])[NH:33][NH:34]4)=[CH:30][CH:29]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2c(=O)[nH][nH]c2c1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: COCCC(C(=O)Nc1ccc2c(=O)[nH][nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (377 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 65 mg (438 μmol, 1.1 eq.) of 6-amino-1H-indazol-3(2H)-one were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol mixtures). Yield: 105 mg (52% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.67 h

Procedure:
2.2 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are dissolved in 10 ml of formic acid, and one g of sodium nitrite is added gradually thereto at 0° to 5° C. for 40 minutes under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.0 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-glucopyranosylurea is thereby obtained as pale yellow caramel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]2.N12CCCN=C1CCCCC2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:12])[O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([C:39](=[O:41])[CH3:40])[N:34]=[CH:33]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Reactant: CC(=O)n1ncc2cc(O)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)n1ncc2cc(OP(=O)(Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc21
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A solution of 2.36 g of phenylphosphonic acid bis-(4-nitrophenyl) ester (prepared according to procedure E) in 60 ml of dichloromethane is cooled in an ice bath. 1.041 g of 1-(5-hydroxyindazol-1-yl)ethanone and 900 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 40 ml of dichloromethane are added thereto and the reaction is continued at 20° C. for 2 hours. The reaction medium is washed with a saturated sodium bicarbonate solution until discoloration of the organic phase. After separation by settling out, the organic extracts are dried over magnesium sulfate and then evaporated under reduced pressure. 2.4 g of phenylphosphonic acid 1-acetyl-1H-indazol-5-yl ester 4-nitrophenyl ester are isolated, which compound is used without purification in the subsequent stage.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:20]=[CH:19][C:13]([CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([NH2:39])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]([OH:18])[C:15](=[O:17])[NH:39][CH:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(C(O)C(=O)O)cc1)c1ccccc1
Reactant: CC(N)CCc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(CCc1ccc(OCc2ccccc2)cc1)NC(=O)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
As pointed out above, a preferred embodiment of this invention employs a mixture of all four optica isomers of the compound of Example 7. This racemic mixture can be prepared by the method described above by reaction of dl-4-(benzoyloxy)mandelic acid with dl-1-methyl-3-(4-benzyloxyphenyl)propylamine in the presence of DCC to give racemic 1-(4-benzyloxyphenyl)-2-oxo-2-[1-methyl-3-(4-benzyloxyphenyl)propylamino]ethanol. Reduction of the latter compound and subsequent removal of the benzyl groups provides racemic 1-(4-hydroxy-phenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]-ethanol. This compound is more preferably prepared by the following procedure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:5][CH:6]=[CH:7][CH:8]=1.Br[C:23]1[N:31]2[C:26]([CH:27]=[N:28][C:29]([S:32][CH3:33])=[N:30]2)=[CH:25][CH:24]=1.CO.C(Cl)Cl>CN(C)C=O.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.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3]1[C:4]([C:23]2[N:31]3[C:26]([CH:27]=[N:28][C:29]([S:32][CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1OC
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccnc1-c1ccc2cnc(SC)nn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
3-Methoxy-2-tributylstannanyl-pyridine (1.31 g, 3.29 mmol) was dissolved in N,N-Dimethylformamide (15 mL), 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.504 g, 2.06 mmol) and Tetrakis(triphenylphosphine)palladium(0) (161 mg, 0.139 mmol) were added, and the mixture was degassed under vacuum, then under an atmosphere of Nitrogen, was heated in a block at 80° C. for 8 h, then 110 C overnight. Bis(tri-tert-butylphosphine)palladium (45 mg, 0.088 mmol) was added and heating was continued at 110 C for 8 h. The mixture was cooled, conc. in vacuo and applied to a 25 g Isco cartridge (MeOH:DCM), dried and purified (80 g column, 0-70% EtOAc:Hex) to afford 7-(3-Methoxy-pyridin-2-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.192 g; Yield=34.1%). LCMS (HPLC):0.78 min, m/z=273 (M+H); 1H-NMR (DMSO-d6): 9.04 (s, 1H), 8.29 (d, 1H, J=4.4 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.50 (dd, 1H, J=4.4, 8.4 Hz), 7.12 (d, 1H, J=4.6 Hz), 7.07 (d, 1H, J=4.6 Hz), 3.83 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C=O.[C:25]([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([NH:15][CH2:16][CH2:17][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:25]=3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)Nc1cccc2c1CC(NCc1ccccc1)CC2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CC(NCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
A mixture of 1-acetamido-7-benzylamino-5,6,7,8-tetrahydronaphthalene (14.3 g, 50 mmol), paraformaldehyde (15 g, 0.5 mol) and sodium cyanoborohydride (15.7 g, 0.25 mol) in acetic acid (250 mL) was stirred at room temperature for 48 h. The solvent was removed and the residue taken up in water:diethyl ether. The aqueous phase was basified with 12.5% NaOH and back extracted with ether. The combined ether layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to give a viscous syrup (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
3-chloro-4-fluoroaniline (10 g, 67.32 mmol) dissolved in CH2Cl2 was added with propionyl chloride (6.6 mL, 74.10 mmol) and triethyl amine (10.2 mL, 73.58 mmol) dropwise under water bath, and the mixture was stirred for 2 h. The resulting solution was washed with water (2×50 mL) and saturated aqueous NaHCO3 solution (12 mL). The CH2Cl2 layer dried over MgSO4 was evaporated to give title compound as light purple solid (13.01 g, 96.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (t, J=7.6 Hz, 3H), 2.30 (q, 7.6 Hz, 2H) 7.31 (dd, J=9.2 and 8.8 Hz, 1H), 7.44 (ddd, J=8.8 and 4 and 2.8 Hz, 1H), 7.91 (dd, J=7.2 and 2.8 Hz, 1H), 10.04 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.4, 29.4, 116.6, 116.8, 118.8, 119.0, 119.1, 120.2, 136.55, 136.58, 151.5, 153.9, 172.1;
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([OH:5])[CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:60]1([NH:63][CH:64]2[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)[CH2:62][CH2:61]1.Cl>O.CN(C=O)C>[CH:64]1([N:63]([CH:60]2[CH2:62][CH2:61]2)[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:16])[F:15])=[CH:14][CH:13]=2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: C1CCC(NC2CC2)CC1
Reactant: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(c1ccc(C(=O)N(C2CCCCC2)C2CC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (0.10 g, 0.43 mmol), HBTU (0.19 g, 0.51 mmol), and HOBt (0.072 g, 0.53 mmol) was added DMF (1 mL) and Hünig's base (0.18 mL, 1.0 mmol). The acid was activated by stirring at room temperature for 5 min. To the activated ester was added N-cyclopropylcyclohexylamine (0.13 g, 0.86 mmol). The reaction mixture was stirred for 1 h, poured into H2O (7 mL), acidified with 5 N HCl and extracted with CH2Cl2 (2 mL). The organic extracts were washed with 1 N NaOH (4 mL), dried with Na2SO4, and removed in vacuo. Silica gel chromatography (gradient 20 to 30% ethyl acetate in hexanes) afforded racemic N-cyclohexyl-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. Chiral HPLC (Chiracel AD-H, isocratic 10% IPA in hexanes) afforded the early eluting R- and late eluting S-isomers,35 mg and 37 mg, respectively. S-isomer: 1H NMR (500 MHz, CDCl3) δ 0.40-0.50 (m, 2H), 0.51-0.61 (m, 2H), 1.12-1.25 (m, 1H), 1.33-1.45 (m, 2H), 1.67-1.75 (m, 2H), 1.79-1.90 (m, 7H), 1.91-2.00 (m, 1H), 2.53-2.6 (m, 1H), 2.83 (s, 1H), 4.03-4.15 (bs, 1H), 7.47 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:40])[CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:40])[CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: OCC1CCCNC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCCC(CO)C5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and racemic 3-piperidinemethanol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=552.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].C(SCC(OC(=O)NC)COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCCCCCCCCC.[Cl:77][CH2:78][CH2:79][CH2:80][S:81](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:83])=[O:82]>>[Cl:77][CH2:78][CH2:79][CH2:80][S:81]([NH:8][CH2:7][CH:6]([O:5][C:3](=[O:4])[NH:2][CH3:1])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:83])=[O:82]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropylamine IV c2 is allowed to react and worked up by the same procedure as described in (4). m.p. 102°-104° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]=1[Cl:31].Cl>CN(C=O)C.C(OCC)C>[CH2:24]([O:23][C:19]1[CH:18]=[C:17]([Cl:31])[C:16]([CH2:15][N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:1]2=[O:11])=[C:21]([Cl:22])[CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NCCC12CCCCC2
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1N(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
Treat a solution of 2-aza-spiro[4.5]decan-1-one (0.50 g, 3.26 mmol) in DMF (8 mL) with 60% sodium hydride (0.20 g, 5.0 mmol) and stir at room temperature for 20 minutes under N2. Cool the reaction to 0° C., treat with 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene (1.24 g, 3.58 mmol), stir for 15 minutes at 0° C., warm to room temperature, and stir for 2 hours under N2. Acidify the reaction with 1 N HCl, dilute the reaction with diethyl ether, and then wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 1.23 g (90%) of the titled product. Rf=0.23 (3/1 ethyl acetate/hexanes). MS (m/z): 418 (M+).
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc(C)cc(CN(C)CC(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(CN(C)CC(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[isobutyl(methyl)amino]methyl}-5-methylbenzoate (120 mg, 0.48 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (200 mg, 4.8 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 236 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>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>[Cl:11][C:4]1[CH:3]=[C:2]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1cc(-c2ccco2)nc2c1CCC2
Temperature: 110 °C
Yield: 92.4 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.130 g, 0.69 mmol) in dioxane (3 mL) was added tributyl(furan-2-yl)stannane (0.271 g, 0.76 mmol) and tetrakis(triphenylphosphine)palladium (0.039 g, 0.035 mmol). The mixture was purged with nitrogen and then heated to 110° C. under sealed conditions for 2 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.140 g, 92%) as a white solid. MW=219.67. 1H NMR (CDCl3, 500 MHz) δ 7.52-7.48 (m, 1H), 7.45 (s, 1H), 7.02-6.98 (m, 1H), 6.52-6.48 (m, 1H), 3.10 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H); APCI MS m/z 220 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:34][CH2:35][CH2:36][S:37](=[O:39])(=[O:38])[NH2:40])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCCS(N)(=O)=O
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 24.6 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (500 mg, 1.042 mmol), 2-aminoethanesulfonamide (142 mg, 1.146 mmol), HATU (594 mg, 1.563 mmol), and Hunig's Base (0.910 mL, 5.21 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-sulfamoylethyl)benzamide (150 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.31-1.42 (m, 4H), 3.34-3.40 (m, 2H), 3.79-3.89 (m, 2H), 4.86-4.92 (m, 2H), 7.20-7.33 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.89 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 585.9.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Br: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][S:18](Cl)(=[O:20])=[O:19]>>[OH:2][CH2:1][CH2:3][NH:4][S:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])(=[O:19])=[O:20]
Reactant: NCCO
Reactant: O=S(=O)(Cl)CCCCCCCCCCCCBr
Product: O=S(=O)(CCCCCCCCCCCCBr)NCCO
Yield: 73.6 %

Procedure:
Ethanolamine (0.67 g, 11 mmol) was reacted with 12-bromododecanesulfonyl chloride (1.74 g, 5 mmol) in the same manner as in Preparation Example 4, to give N-(2-hydroxyethyl)-12-bromododecanesulfonamide (1.37 g) as colorless crystals.
Reaction SMILES: [C:1]([N:9]([CH2:11][C:12](O)=O)[CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:22]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[CH:24]=C1>C1(C)C=CC=CC=1>[CH3:10][N:9]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:24]2[C:12]([C:22](=[O:33])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]2=[O:32])=[CH:11]1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CN(CC(=O)O)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cn1cc2c(c1-c1ccccc1)C(=O)c1ccccc1C2=O
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
N-Benzoylsarcosine (3.86 g, 0.020 mol) was dissolved in 7 mL (0.070 mol) of acetic anhydride and heated until a yellow color was observed. Forty milliliters of toluene was added to the reaction flask after the color change was observed. After stirring for 15 minutes, 3.16 g (0.020 mol) of 1,4-naphthoquinone was added. The resulting black mixture was heated for 1.5 hours, then stirred at room temperature overnight. The mixture was filtered to yield 1.13 g (19%) of yellow-brown solid. The solid was recrystallized several times from toluene to give bright yellow crystals: mp 268°-271° C.; IR 1655 and 1645 (C=0) cm-1 ; H-1 NMR (CDCl3) δ 3.60 (s, 3, NCH3), 7.10-7.75 (complex m and s, 8, ArH and pyrrole H), 7.95-8.30 (m, 2, ArH); MS m/e 287 M+.