Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.CCOCC.C(=O)(O)[O-].[K+]>O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:15]2[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCCN(c2nc(Cl)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 3.16 g (0.02 mole) of piperidine-3-carboxylic acid ethyl ester, 3.71 g (0.019 mole) of 2,4-dichloro-5-nitro-pyrimidine and 60 mL of ether at 5 degrees, was added a solution of 4 g (0.04 mole) of potassium bicarbonate in 40 mL of water was added over 25 minutes. The mixture was stirred for an additional 1 hour, then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-88:12) to give 3.99 g of (rac)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (IV-67).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1Br)(=[O:34])[CH3:33]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1[C:6]1[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:20][N:19]=2)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=1)(=[O:34])[CH3:33]
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
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: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 29.9 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 198f (244 mg, 0.58 mmol), 198d (200 mg, 0.46 mmol), Pd(PPh3)4 (33 mg, 0.030 mmol) in 2 N Na2CO3 (1 mL) and DME (2 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:MeOH, 85:15) to give 30% (90 mg) of 198g as solids.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][N:69]([CH3:75])[CH2:70][CH2:71][C:72](O)=[O:73].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:72](=[O:73])[CH2:71][CH2:70][N:69]([CH3:75])[CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: CN(C)CCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), N,N-dimethyl-beta-alanine (0.016 g, 0.103 mmol) and diisopropylethylamine (0.11 mL, 0.617 mmol) in DMF (1 mL). the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give a white solid. Purification by reverse phase HPLC (acetonitrile:water with 0.1% TFA) gave the title compound (0.024 g, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 10.04 (s, 1H), 9.17-9.45 (m, 1H), 8.96 (t, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.42-7.50 (m, 2H), 7.29-7.40 (m, 2H), 7.23 (d, 1H), 7.08 (s, 1H), 4.53 (d, 2H), 3.31-3.39 (m, 2H), 2.71-2.82 (m, 8H). ES MS: m/z 568 (M+1).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C([Sn](=O)CCCC)CCC.Br[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=1[C:23]([O:25][CH3:26])=[O:24].[F-].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O.O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH2:2]1
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: OC1CCCC(O)C1
Agent: CCCC[Sn](=O)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.7 g of 1,3-cyclohexanediol and 12 g of dibutyltin oxide are dissolved in 600 ml of toluene and heated to the boil under reflux on a water separator. During the reaction, the reaction volume is reduced to half the original volume. After 4 hours, the reaction mixture is cooled to room temperature and 300 ml of dimethylformamide, 9.0 g of methyl 2-bromomethyl-6-methylbenzoate and 9.4 g of cesium fluoride are added. The mixture is stirred at room temperature for 12 hours. The reaction mixture is diluted by addition of ethyl acetate and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, the solvent is reduced under reduced pressure and the residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=50:1→1:2). This gives 6 g of methyl 2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate as an oil. C16H22O4 (278.35), MS(ESI): 279 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:36][CH:35]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (2.1 g, 9.9 mmol) and triphenyl phosphine (2.59 g, 9.9 mmol) were dissolved in dry THF (35 ml) under nitrogen. The solution was cooled to 0° C. and 4-chlorophenol (1.28 g, 9.9 mmol) dissolved in dry THF (10 ml) was added followed by diethyl azodicarboxylate (DEAD) (1.55 ml, 9.9 mmol). After 15 minutes the ice bath was removed and the reaction was stirred overnight The reaction mixture was concentrated under reduced pressure and the residue was stirred with ether. The solid triphenyl phosphine oxide was filtered off. The solution was washed three times with sodium hydroxide (1M) and concentrated. The BOC-protected product was purified by flash chromatography on silica using EtOAc/heptane as eluant. It was dissolved in dichloromethane (35 ml) and trifluoroacetic acid (17 ml). The reaction mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography on silica (MeOH:CHCl3:NH3, 100:100:1) to give the subtitle compound (1.72 g, 88%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH2:17][CH2:16]2)[N:12]=[C:11]([Cl:18])[C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(O)=O.[Fe]>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH2:16][CH2:17]2)[N:12]=[C:11]([Cl:18])[C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Benzyl-(2-chloro-6-cyclopropyl-3-nitro-pyridin-4-yl)-amine (245 mg, 0.8 mmol) was dissolved in AcOH:H2O (9.0:0.9 mL). Iron powder (270 mg, 4.8 mmol) was added and the mixture was vigorously stirred at room temperature under a nitrogen atmosphere over the weekend, during which an off-white precipitate had precipitated out. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL), the mixture filtered through celite, and the filter cake washed with EtOAc (20 mL). The phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was dried in vacuo at 40° C. overnight to give the title compound (215 mg) as an off-white crystalline solid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])C1C=CC=CC=1.Br.CCOCC>C(O)(=O)C>[NH2:10][C@H:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26]
Reactant: O=C(N[C@H]1CCN(CCc2ccccc2)C[C@H]1C(=O)N1CCSC1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N[C@H]1CCN(CCc2ccccc2)C[C@H]1C(=O)N1CCSC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
(3R,4S)-[1-Phenethyl-3-(thiazolidine-3-carbonyl)-piperidine-4-yl]-carbamic acid benzyl ester (216 mg) was treated with 33% HBr in acetic acid (2.5 ml) for 2 hours at RT under argon. Ether (15 ml) was added and the resulting suspension was cooled to −10° C. and stirred for 1 hour. The solvent was then decanted and the solid washed with a small amount of EtOH. The residue was then dissolved in water (pH was adjusted to 10 with conc. NH4OH) and the aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated to give a residue that was purified by flash chromatography (gradient of MeOH in DCM containing 0.5% NH4OH) to furnish the desired product as a light yellow oil (92 mg). MS (ESI): 320.1 MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:49]([NH2:52])([CH3:51])[CH3:50]>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[NH:52][CH:49]([CH3:51])[CH3:50])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CC(C)N
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: CC(C)NC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and isopropylamine.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH:10][C:11]1[N:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[C:26]([Cl:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=3[Cl:32])[CH:17]=2)[N:12]=1)=[N+]=[N-]>CO.CCOC(C)=O.[Pd]>[Cl:27][C:26]1[C:25]([O:28][CH3:29])=[CH:24][C:23]([O:30][CH3:31])=[C:22]([Cl:32])[C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:5]1[C@@H:4]([NH2:1])[CH2:9][CH2:8][O:7][CH2:6]1)[N:20]=[CH:19]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N=[N+]=[N-])ncc3c2)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N)ncc3c2)c1Cl
Reaction time: 1 h
Yield: 100.8 %

Procedure:
N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-amine (0.063 g, 0.133 mmol) was taken up in Methanol (7 ml) and EtOAc (7.00 ml), Pd—C (0.014 g, 0.133 mmol) was added and stirred under a H2 balloon for 1 hour. After the reaction was completed, it was filtered through celite and the solvent removed. (3S,4S)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydro-2H-pyran-3,4-diamine (0.060 g, 0.134 mmol, 101% yield) was recovered as a yellow solid, which was carried on without further purification. MS (ES+) C21H22Cl2N4O3 requires: 448, found: 449 [M+H]+.
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccccc3)CC2)CC1

Procedure:
From 4-benzoylpiperidine hydrochloride (200 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 235 mg) by procedure A.2. Yield: 181 mg (49%). Off-white solid. MS (m/z): 415.3 ([M+H]+).
Reaction SMILES: C([SiH](CC)CC)C.O=[C:9]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]>FC(F)(F)C(O)=O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)[CH3:22]
Reactant: CCc1ccc(C(=O)CCC(=O)O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 86 h

Procedure:
In a 100-cm3 flask, 2.5 g of 4-oxo-4-(4-ethylphenyl)butyric acid are dissolved with magnetic stirring in 19 cm3 of trifluoroacetic acid. 3.2 g of triethylsilane are added dropwise. The reaction mixture is stirred for 86 hours at room temperature. It is poured into ice. It is extracted with 3 volumes of ether. The organic phases are washed 3 times with 10% potassium carbonate solution. The aqueous phases are combined and then acidified by adding concentrated hydrochloric acid until the pH is 3-4. The precipitate obtained is drained and then recrystallized.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)s1
Reaction time: 0.3 h
Yield: 78.9 %

Procedure:
To a solution of 1.76 g (5.60 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid and 30 mL of dimethylformamide was added 2.75 g (7.01 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.0 mL (17.2 mmole) of ethyldiisopropylamine. The mixture was stirred for 18 minutes, then 0.4541 g (8.49 mmole) of ammonium chloride was added. The mixture was concentrated under reduced pressure and diluted with 350 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100:0) to give 1.384 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([O:16][C:17](=[O:28])[C@H:18]([CH3:27])[NH:19]C(=O)CC(C)CC)[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:28])[C@H:18]([CH3:27])[NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)cc1

Procedure:
Following General Procedure B and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example 3 above), the title compound was prepared as a solid having a melting point of 111°-113° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:22][CH:21]3[CH:16]([CH2:17][CH2:18][C:19]4[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=43)[CH2:15]2)=[O:13])=[CH:6][CH:5]=1)([O-])=O>[Ni].COCCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:22][CH:21]3[CH:16]([CH2:17][CH2:18][C:19]4[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=43)[CH2:15]2)=[O:13])=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1OC)CCC1CN(C(=O)CCc3ccc([N+](=O)[O-])cc3)CC21
Agent: [Ni]
Solvent: COCCO
Product: COc1ccc2c(c1OC)CCC1CN(C(=O)CCc3ccc(N)cc3)CC21
Reaction time: 0.5 h

Procedure:
A mixture of the compound of example 14 (1.83 g, 4.5 mmole), 2 g of Raney Nickel, and 250 mL of 2-methoxyethanol was hydrogenated at 3 atmospheres in a Parr shaker for 0.5 hour. The resulting mixture was filtered and evaporated to give 1.8 g (71%) as a brown oil; M+ 380.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:48])([CH2:42][N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)[C@H:23]([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[O:28][CH2:27]1)[CH3:24]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:39]=[CH:40][CH:41]=[C:32]([C@H:29]3[O:28][CH2:27][C@H:26]([S:25][C@H:23]([CH3:24])[C@:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[F:14])([OH:48])[CH2:42][N:43]4[CH:47]=[N:46][CH:45]=[N:44]4)[CH2:31][O:30]3)[CH:33]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2cccc(C(=O)Nc3ccc(C#N)cc3)c2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4) a reaction was carried out using commercially available 4-aminobenzonitrile (138 mg, 1.2 mmol), trimethylaluminium (1.08 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 3-[trans-5-[[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (147 mg, 0.29 mmol), obtained in Example 6(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (162 mg, yield 94%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([O-:21])=[O:20])=[N:17][CH:18]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[CH3:28][CH2:29][CH:30](O)[CH2:31][CH3:32]>S(=O)(=O)(O)O>[C:1]1([S:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH:30]([CH2:31][CH3:32])[CH2:29][CH3:28])=[O:20])=[N:17][CH:18]=2)=[O:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(O)CC
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc(C(=O)[O-])nc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCC(CC)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccccc2)cn1
Temperature: 90 °C

Procedure:
5 drops of concentrated sulfuric acid were added to 0.9 g (2.94 mmol) of 5-[((phenylsulfonyl)amino)carbonyl]-pyridine-2-carboxylate in 30 ml of 3-pentanol, while stirring, and the mixture was heated at 90° C. for 6 hours. The excess 3-pentanol was distilled off in vacuo and the residue was treated with ethyl acetate. The crystalline crude product was combined with the product obtained from the mother liquor by purification by column chromatography (melting point 186° to 187° C.), treated with hot ethyl acetate, cooled, filtered off with suction and washed with ethyl acetate. This gave 0.55 g of the colorless title compound, melting point 182° to 183° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:28]=[CH:29][C:3]([CH2:2][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:4][CH:5]=2)[S:11][C:12]=1[C:20]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CCl)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CN2CCCCC2)cc1
Yield: 140.1 %

Procedure:
Compound 478 (340 mg, 0.789 mmol) was suspended in THF (3 mL), and piperidine (0.390 mmol, 3.95 mmol) was added thereto, followed by stirring under heating and reflux for 1.5 hours. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=4:1), followed by reslurrying with diethyl ether to afford the entitled Compound 480 (262 mg, 69%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:20][C:21]([OH:23])=[O:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]sulfinyl}acetate (0.12 g, 0.30 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added to the mixture. The obtained crystals were recrystallized from ethanol to give the titled compound (0.081 g, 79%) as pale yellow crystals.