Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-])=O)=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>O=[Pt]=O.C1COCC1>[NH2:1][C:4]1[CH:66]=[CH:65][C:7]([O:8][P:9]2([O:55][C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=3)([O:35][C:36]3[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=N2)cc1

Procedure:
A 1000-mL stirrer-equipped autoclave was charged with 40.0 g (0.041 mol) of hexakis(4-nitrophenoxy)cyclotriphosphazene (2), aniline (75 mL), and 0.1 g of PtO2 catalyst. The mixture was agitated vigorously under 50 psi of hydrogen pressure at 50° C. until no further pressure drop was recorded (~30 h). The reaction mixture was filtered and the filtrate was poured slowly into toluene (1000 mL). Impure 3 precipitated from solution. After filtration, the crude 3 was recrystallized from o-dichlorobenzene and from THF to yield 30 g (92%) of pure 3, mp 189°-190° C. A 31P NMR spectrum in THF showed a singlet at 11.2 ppm, which indicated complete conversion of NO2 to NH2 groups.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.CN(C)C=O.[C:28](=[N:31]O)([NH2:30])[CH3:29]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][N:31]=[C:28]([CH3:29])[N:30]=4)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CC(N)=NO
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2cc(F)ccc2-3)n1
Reaction time: 1.5 h

Procedure:
8.60 g (28.5 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid, 30 ml of N,N-dimethylformamide and 6.16 g (38 mmol) of N,N'-carbonyldiimidazole are stirred at room temperature for 45 minutes and at 55° for 1 hour. 2.44 g (33 mmol) of acetamidoxime are subsequently added and the mixture is stirred at 75° for a further 1.5 hours. The mixture is poured into 200 ml of water, stirred for 20 minutes, suction filtered and the filter residue is dried. 8.60 g of the thus-obtained product are stirred at 115° for 2.5 hours in 50 ml of glacial acetic acid. The solution is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained (S)-7-fluoro-11,12,13,13a-tetrahydro-1-(3-methyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 248°-249°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]1[C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[S:22][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 382.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH2:20]([O:22][P:23]([O-:27])[O:24][CH2:25][CH3:26])[CH3:21].C(N(CC)CC)C>[Pd].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([P:23]([O:24][CH2:25][CH3:26])([O:22][CH2:20][CH3:21])=[O:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(I)cc12
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(P(=O)(OCC)OCC)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
1.46 g of 6-iodo-beta-carboline-3-carboxylic-acid-ethylester is added anhydrously to a mixture of 608 g of diethylphosphite, 448 g of triethylamine, 240 mg of palladium tetrakristriphenylphosphine and 60 ml of N-methyl-2-pyrrolidone and is stirred for 12 h at 90° C. After concentration is an oil pump vacuum, the residue is chromatographed on 75 g of silica gel with methylene-chloride/acetone in the ratio of 1/1 as the eluant. The corresponding consolidated fractions are chromatographed on 25 g of silica gel with methylene-chloride/ethanol=10/2 as the eluant. 421 mg of 6-diethoxyphosphoryl-beta-carboline-3-carboxylic-acid-ethylester in the form of an oil is obtained.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]=[C:11]=[S:12]>C1C=CC=CC=1>[CH3:9][NH:10][C:11](=[S:12])[NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CN=C=S
Solvent: c1ccccc1
Product: CNC(=S)NNc1ccccc1
Yield: 67.4 %

Procedure:
In 500 ml of benzene was dissolved 108 g of phenylhydrazine, and 73 g of methyl isothiocyanate was added dropwise to the solution, followed by heat refluxing. As the reaction proceeded, crystals were preicpitated. The thus formed crystals were filtered and dried to obtain 122 g of 4-methyl-1-phenylthiosemicarbazide.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:5]([O:4][C:2]([NH:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCC(O)C1=CC2(CCCC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)NCC(O)C1=CC2(CCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
Ethyl chloroformate (2.06 g) is added dropwise at about 7° C. to a stirred mixture of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (3.35 g) in chloroform (50 ml) and sodium hydroxide (0.9 g) in water (20 ml). After 2 hours, the chloroform phase is separated and the aqueous phase is extracted twice with chloroform. The combined chloroform solutions are dried and concentrated under reduced pressure. The crude 2-ethoxycarbonylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol thus obtained is dissolved in tetrahydrofuran (50 ml) and added dropwise to lithium aluminium hydride (1.8 g) in tetrahydrofuran (150 ml). After refluxing for 3 hours, the mixture is cooled and decomposed with a slight excess of saturated sodium sulphate solution. The solid precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried and the solvent is removed, finally under reduced pressure. The residual oil crystallizes on scratching. Crystallization from diisopropyl ether gives the title compound; m.p. 134° C. 2-Ethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is similarly obtained when using acetic anhydride instead of ethyl chloroformate and reduction of the crude N-acetyl derivative. The free base is obtained as an oil, which is converted to the hydrochloride by treatment with hydrogen chloride in diethyl ether, m.p. 227° C. after crystallization from isopropyl alcohol. An identical product is obtained by reduction of crude 2-acetamido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol acetate obtained by the treatment of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol with acetylchloride in diethyl ether containing an excess of triethylamine, removal of the precipitated triethylamine hydrochloride by filtration and evaporation of the filtrate.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])[CH2:4][CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:61][N:62]([CH2:72][CH:73]=O)[C:63](=[O:71])[CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:69]([O:68][C:66](=[O:67])[CH2:65][CH2:64][C:63]([N:62]([CH3:61])[CH2:72][CH2:73][N:6]([CH2:7][C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])[CH:3]([CH2:2][CH3:1])[CH2:4][CH3:5])=[O:71])[CH3:70]
Reactant: CCC(CC)NCc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CCOC(=O)CCC(=O)N(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of 1.00 g of methyl 4-{2-[4-({[2-({3-[(pentan-3-ylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.00 g of sodium triacetoxyborohydride, 0.50 mL of acetic acid and 20 mL of methylene chloride was added 473 mg of ethyl 4-[methyl(2-oxoethyl)amino]-4-oxobutanoate, followed by stirring for 1 hour at room temperature. 498 mg of sodium triacetoxyborohydride and 237 mg of ethyl 4-[methyl(2-oxoethyl)amino]-4-oxobutanoate were further added to the reaction mixture, followed by stirring for 2 hours at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), thereby obtaining 1.19 g of methyl 4-(2-{4-[({2-[(3-{[{2-[(4-ethoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidine (example A.46) (1.5 g, 5.09 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.96 g, 6.1 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.51 g, 27%). MS (ISP) 372.0 [(M+H)+]; mp 151.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1.Cl[CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Reactant: CC(C)(C#N)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(Cl)ccc21
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a stirred solution of potassium t-butoxide (0.561 g, 5.00 mmol, 1.2 eq) in anhydrous DMSO (16 mL) was added 5′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.00 g, 4.17 mmol) all in one portion. After stirring 10 min. 3-chloro-2,2-dimethylpropionitrile (0.981 g, 8.34 mmol, 2 eq) was added in one portion at room temperature under a dry N2 atmosphere. The reaction was heated at 125° C. for 22 hr, cooled to room temperature, poured into H2O (180 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 100% CH2Cl2 to give the title compound as a white solid (0.91 g, 68% yield). Anal. Calc'd for C16H17ClN2O3: C, 59.91; H, 5.34; N, 8.73. Found: C, 59.79; H, 5.26; N, 8.57. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES+) m/z 321 [M+H]; one Cl pattern observed. m.p.: 114-115.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(=O)(O)[O-].[Na+].O.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1
Reactant: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc([N+](=O)[O-])cc12
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1
Reaction time: 4 h

Procedure:
The nitroxanthone from step (B) (1.55 g) was dissolved in a solution of sodium bicarbonate (0.42 g) in water (150 ml) with warming. To the solution was added 10% palladium on carbon catalyst and the solution hydrogenated at room temperature and atmospheric pressure for 4 hr, during which time hydrogen uptake was measured as 440 ml. The solution was filtered and the filtrate acidified with twice-normal hydrochloric acid solution. The amino-compound was filtered from the warmed mixture, washed well with water and dried to yield 0.98 g, mpt. 296°-297° C. with decomposition.
Reaction SMILES: C([O-])(=O)C.[Na+].[N-:6]=[N+:7]=[N-:8].[Na+].CN(C=O)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][C@H:24]1OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O>[N:6]([C@H:28]1[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:27]1)=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
Sodium acetate (204 mg) and sodium azide (161 mg) were added to a DMF (5 mL) solution containing (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)piperidin-1-carboxylate (532 mg), followed by stirring at 80° C. for 4 hours. The pH of the reaction solution was adjusted to pH 12 with the addition of water and a 2M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of (cis)-benzyl 3-azido-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (124 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:42](=[O:43])[NH:41][CH:38]3[CH2:40][CH2:39]3)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C=NC1CC1
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(=O)NC4CC4)cnn23)c1
Yield: 45.8 %

Procedure:
Using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.19 mmol) obtained in Example 31 step 5 and cyclopropylisocyanate (0.048 g, 0.57 mmol) instead of ethylisocyanate, and in the same manner as in Example 7, the title compound (0.053 g, 62%) was obtained.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[O:15])[CH2:8][S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1nccs1
Solvent: ClCCl
Product: CCOC(=O)C(=O)CSC1=NCCS1
Yield: 94.3 %

Procedure:
A solution of 2-mercaptothiazole (238 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (7 mL) was shaken at 20° C. for 3 hours under nitrogen. The obtained solid was filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (440 mg, yield 71%) as a solid. 1H-NMR (300 Hz, D3COD) δ (ppm): 4.63 (d, J=13.1 Hz, 1H), 4.30-4.15 (m, 6H), 4.10 (d, J=13.1 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI) m/z: 234 (M+H, 100).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:3][C:4]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1sc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(N2CCOCC2)nc1Br
Yield: 43.8 %

Procedure:
A mixture of 2,4-dibromothiazole-5-sulfonamide (0.515 g, 1.60 mmol), morpholine (0.153 mL, 1.76 mmol), THF (4.22 mL) and cesium carbonate (1.56 g, 4.80 mmol) in a sealed tube was heated to 80 degrees for 4 hours. The cooled reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organic layer was washed with water (15 mL), dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→50/50) to give 230 mg (44% yield) of the title compound as a white solid. LC/MS (FA) ES+ 328, 330. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (s, 2H), 3.69-3.66 (m, 4H), 3.43-3.40 (m, 4H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (25 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.687 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.92 (s, 1 H), 6.34 (s, 1 H), 3.87 (s, 3 H), 3.1-2.9 (m, 6 H), 2.75 (m, 1 H), 2.60 (bs, 1 H), 1.31 (d, J=7 Hz, 3 H). MS calculated for C12H16BrNO+H: 270, observed: 270.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=1>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCCCO)cc1
Reactant: BrCCCCCCBr
Product: COc1ccc(CCCCOCCCCCCBr)cc1

Procedure:
(3.3 g), b.p. 180°-190°/0.5 torr, from 1,6-dibromohexane (8 g) and 4-(4-methoxyphenyl)butanol (2 g).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1>C(O)(=O)C>[F:3][C:4]1([CH:12]([Br:1])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1
Reactant: BrBr
Reactant: CSC1=NC=CC(F)(CC(=O)c2ccccc2)N1
Solvent: CC(=O)O
Product: CSC1=NC=CC(F)(C(Br)C(=O)c2ccccc2)N1
Yield: 99.7 %

Procedure:
Bromine (1.22 g; 7.6 mmol) in acetic acid (5.6 ml) is added to a solution of 4-Fluoro-2-(2-methylthio-4-pyrimidinyl)acetophenone (2 g; 7.6 mmol) in acetic acid (40 ml). The initially thick precipitate is almost dissolved after 20 min., filtered and the filtrate evaporated to dryness. The residue is taken up in a saturated solution of NaHCO3 and extracted three times with tert.butyl methyl ether. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield 2.6 g (100%) of a brown oil, which is used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][C:13]([CH3:15])=O.N1CCCCC1>N1C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:13]([CH3:15])([CH3:12])[CH2:10][C:9]2=[O:11]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC1(C)CC(=O)c2cc(O)ccc2O1
Reaction time: 48 h
Yield: 75.7 %

Procedure:
To a 250 mL, 2-necked round bottom flask equipped with a magnetic stir bar and a water-jacketed condenser capped with a balloon was added 2′,5′-dihydroxyacetophenone (2, 8.00 g, 52.6 mmol), reagent grade acetone (19.45 mL, 263 mmol), piperidine (5.2 mL, 52.6 mmol) and freshly distilled pyridine (50 mL). The mixture was heated to a vigorous reflux with stirring under a nitrogen atmosphere for 2 d. The solvent was evaporated and the concentrate was dried under high vacuum. Reagent grade acetone (19.45 mL, 263 mmol), piperidine (5.2 mL, 52.6 mmol) and freshly distilled pyridine (50 mL) were added, and vigorous reflux with stirring under a nitrogen atmosphere was continued for 2d more. The solvent was evaporated, ethyl acetate (30 mL) and 30% aqueous CuSO4 (30 mL) were added to the concentrate. The organic phase was washed with brine (1×30 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 2:1 hexanes/ethyl acetate as eluent (Rf=0.3). The product gives off a purple color on an analytical silica gel plate illuminated with a short wave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 7.65 g of 3 (76%) as a brown solid. 1H NMR (300 MHZ, CDCl3): δ 7.32 (m, 1H), 7.04 (m, 1H), 6.82 (m, 1H), 5.48 (bs, 1H), 2.68 (s, 2H), 1.42 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 193.8, 154.4, 149.9, 125.2, 120.0, 119.6, 110.7, 79.0, 48.7, 26.5; HRMS (EI+): calculated for C11H12O3 [M+] m/z 192.0786, found 192.0788.