Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Si:13]([O:20][CH2:21][CH:22]=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[C:16]([Si:13]([CH3:15])([CH3:14])[O:20][CH2:21][CH2:22][NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Tryptamine (3.34 g, 20.85 mmol) and t-butyldimethylsilyloxylacetaldehyde (2.44 g, 13.99 mmol) is dissolved in dichloromethane (200 ml) for 10 minutes. The mixture is cooled to 0° C. and it is added sodium triacetoxyborohydride (5.38 g, 25.38 mmol). The mixture is warmed slowly to room temperature and stirred for 18 hours. Then water is added and the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The crude product is purified by a silica gel flash chromatograph using dichloromethane-methanol eluent.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[CH2:32][CH2:31][CH2:30]1.Cl(O)(=O)(=O)=O>O1CCCC1.CCCCCC>[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]([CH:2]=[O:3])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCSc2ccccc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC1CCCSc2ccccc21
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
A solution of 20.0 g of methoxymethyltriphenylphosphonium chloride in 60 ml of absolute tetrahydrofuran was treated dropwise at 20° C. under argon with 43 ml of 1.4N n-butyllithium in hexane. The mixture was stirred for 1/4 hour. Thereafter, the mixture was treated with 8.02 g of 3,4-dihydro-1-benzothiepin-5(2H)-one in a small amount of tetrahydrofuran. After 5 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 11/2 hours. Thereafter, the reaction mixture was partitioned between petroleum ether and ethanol/water (8:2). The lighter phase was washed with water, dried over sodium sulfate and evaporated. There were obtained 11.8 g of crude product which were dissolved in 80 ml of tetrahydrofuran and treated under argon with 100 ml of 35% perchloric acid. The reaction mixture was stirred overnight, poured on to ice, extracted with ether, washed with 5% sodium carbonate solution, dried and evaporated. Chromatorgraphy on silica gel (petroleum ether/ethyl acetate 92:8) yielded 5.04 g of 2,3,4,5-tetrahydro-1-benzothiepine-5-carboxaldehyde as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][C@H:13]([CH3:16])[CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][C@@H:13]([CH3:16])[NH:14][CH2:15][C@@H:10]2[CH3:9])[CH:7]=[N:6][CH:5]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cncc(Cl)n2)[C@@H](C)CN1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-dichloropyrazine (0.40 g, 2.68 mmol), trans-2,5-dimethylpiperazine (0.62 g, 5.43 mmol), K2CO3 (0.41 g, 3.0 mmol) in acetonitrile (5 mL) was stirred at 90° C. for 6 h in a sealed pyrex tube. After cooling, the reaction mixture was filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. This furnished 0.15 g (25%) of the title compound as an oil. HRMS m/z calcd for C10H15ClN4 (M)+ 226.0985, found 226.0983.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH3:13].[F-:14].[K+].CS(C)=O>C1C=CC=CC=1>[F:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH3:13]
Reactant: [F-]
Reactant: Cc1c(F)c(F)cc([N+](=O)[O-])c1Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: Cc1c(F)c(F)cc([N+](=O)[O-])c1F
Reaction time: 3.5 h
Yield: 48.9 %

Procedure:
To 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) are added spray-dried potassium fluoride (1.4 g), anhydrous dimethylsulfoxide (10 ml) and benzene (10 ml), and the moisture is removed by azeotropic distillation together with benzene. Subsequently, the mixture is stirred at 170°-180° C. under argon stream for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with diethyl ether. The extract is washed with water, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, n-hexane) to give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1>>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:50][C:45]([CH2:44][O:43][NH:42][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=2)[C:30]([OH:32])=[O:31])=[CH:46][CH:47]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NOCc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCc1ccc(-c2ccccc2)cc1
Yield: 41.3 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (91 mg, 0.16 mmol) and 4-[(aminooxy)methyl]-1,1′-biphenyl hydrochloride (46 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (47 mg). 1H-NMR (400 MHz, CD3OD-Me2SO-d6) d 7.74-7.16 (17H), 4.84 (1H), 4.76 (1H), 4.64 (s, 2H), 4.32 (m, 1H), 3.03 (m, 3H), 1.41 (s, 9H); IR (KBr) 3272, 2978, 1681, 1652 cm−1; HRMS m/z 711.2831 (calc. of monoisotopic mass for C39H41N3O10 gives 711.2792).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.O.[CH2:12]1[CH2:16]OC[CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:16][CH:12]=[CH2:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: C1CCOC1
Solvent: O
Product: C=CCCc1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
A 176 g portion of 3,5-difluorobenzyl bromide was dissolved in 300 ml of THF to which was subsequently added dropwise 450 ml of allyl magnesium chloride THF solution (2 mol/l) at room temperature. This was stirred for 1 hour and then mixed with 300 ml of water. This was extracted with 800 ml of hexane, washed twice with saturated brine and then dried with anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was distilled (79-82° C./20 mmHg) to obtain 104 g of 3,5-difluoro-1-(3-butenyl)benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Yield: 107.9 %

Procedure:
A mixture of 2-nitrobenzaldehyde (3.023 g), benzyl acetoacetate (3.802 g) and piperidine (272.5 mg) in benzene (10 ml), was treated in a substantially similar manner that of Example 1-11) to give a brown oil (6.94 g) of benzyl 2-(2-nitrobenzylidene)acetoacetate, which was further treated with ethyl 3-amino-4,4-diethoxycrotonate (4.34 g) to give a dark brown oil (10.3 g). This oil was purified by column chromatography on silica-gel and the resultant oil (3.8 g) was crystallized to give crystals (1.65 g) of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 103° to 103.5° C. (recrystallized from a mixture of diisopropyl ether and n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][C:16]([NH:18][NH2:19])=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C[Si]([N:25]=[C:26]=[O:27])(C)C>ClCCl.C(N(C(C)C)CC)(C)C>[C:26]([NH:19][NH:18][C:16](=[O:17])[CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:20])(=[O:27])[NH2:25]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1c(N2CCCC2CC(=O)NN)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCCC2CC(=O)NNC(N)=O)ccc(C#N)c1Cl

Procedure:
To a solution of 2-[1-(3-chloro-4-cyano-2-methylphenyl)pyrrolidin-2-yl]acetohydrazide (0.288 g, 1.030 mmol) in dichloromethane and diisopropylethylamine, add trimethylsilyl isocyanate (0.238 g, 2.060 mmol) and stir the reaction at 21° C. for 2 h. Partition the reaction is between ethyl acetate and brine. Dry the organic phase over magnesium sulphate, filter, and remove the solvent is under reduced pressure to yield the title compound. (0.303 g, 91%) mass spectrum (m/e): 322.1 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.37 (s, 1H) 7.38 (d, 1H), 7.30 (s, 1H), 6.34 (d, 1H), 5.04 (s, 2H), 4.34 (t, 1H), 3.86 (m, 1H), 3.08 (m, 1H), 2.46 (m, 1H), 2.42 (s, 3H), 2.03 (s, 3H), 2.20-1.85 (m. 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:33]=[C:34]=[O:35])[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][CH2:30][CH2:31][CH3:32]>>[CH2:15]([NH:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:35])[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][CH2:30][CH2:31][CH3:32]
Reactant: NCCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCCCCCCCN

Procedure:
12 grams 1,12 diaminododecane was reacted with 5 gms octadecyl isocyanate as in Example 2. Yield: 13.8 gms., melting point 105°-159°C.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[C:15]1([S:21]([N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 29.9 %

Procedure:
To 4.5 g of 5-ethoxypyrrolidin-2-one dissolved in 140 cm3 of anhydrous tetrahydrofuran, 21.8 cm3 of butyl-lithium in hexane (1.6M) is added drop by drop under an inert atmosphere, while cooling to about -10° C. After 45 minutes, 6.15 g of benzenesulphonyl chloride in tetrahydrofuran is added, and the whole is kept at -10° C. under agitation for 2 hours. It is then returned to ambient temperature, and the residue, after concentrating under reduced pressure, is taken up in 100° ethanol. By cooling and under agitation, the product precipitates, and is then filtered, washed abundantly with water, dried, and 2.8 g of the expected product is obtained after crystallizing from isopropanol, m.p. 112°-113° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:16]=[CH:15][C:14]([NH:17][CH:18]=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]1[N:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]2=[O:26]
Reactant: CCOC(=O)C(=CNc1ccc(NC2Cc3ccccc3C2)nc1)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(NC3Cc4ccccc4C3)nc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
A solution of diethyl 2-((6-(2,3-dihydro-1H-inden-2-ylamino)pyridin-3-ylamino)methylene)malonate (1.3 g) in dichloromethane (10 ml) was added very carefully into pre-heated (230° C.) diphenyl ether (20 ml) with stiffing and heating was continued with stiffing for another 20 min after addition had been completed. This was then allowed to cool to room temperature, petroleum ether (200 ml) was added, and the solid which separated was filtered off dried to give the crude product (600 mg), which was on-reacted without further characterization other than ascertaining that the compound was one spot by tlc with the expected molecular weight (M+1) of 350.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26])=[O:33])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: CCOC(=O)CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and ethyl bromoacetate. MS: ESI (negative): 441 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6](I)=[CH:5][CH:4]=1.[CH3:22][C:23]1[CH:28]=[C:27]([Sn](C)(C)C)[CH:26]=[CH:25][N:24]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: Cc1cc([Sn](C)(C)C)ccn1
Product: COc1ccc(-c2ccnc(C)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 50 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-iodo-benzothiazol-2-yl)-amide (260 mg, 0.60 mmol) and 2-methyl-4-trimethylstannanyl-pyridine (384 mg, 0.90 mmol) using the general procedure B as a light yellow solid in 50% yield. MS: m/e=396 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][OH:29])[NH2:27])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:22][O:24][C:25](=[O:30])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH2:28][OH:29]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CO)NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16]Br>>[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CC(C)CCBr
Reactant: OCCCCCCCCCCBr
Product: CC(C)CCCCCCCCCCCCO
Yield: 62 %

Procedure:
13-methyltetradecan-1-ol was prepared from 10-bromodecanol and 3-methylbutylbromide in 62% yield. The 1H NMR and MS-ESI data matched those reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour and Fragrance Journal 19:199-204).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH2:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCNCCC(=O)OCC
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(CC)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
7.8 g of sodium carbonate are added to a solution of 10 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline, prepared as described in Application Example 1, and 9.7 g of N-ethyl-N-(b-ethoxycarbonylethyl)amine in 120 cm3 of toluene. The suspension obtained is heated to approximately 90° C. and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 100 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 13 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-ethyl-N-(b-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: O[C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:8][CH:7]2[N:9](C(OC(C)(C)C)=O)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1>ClCCl.C(#N)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]1[CH2:3][CH:4]2[NH:9][CH:7]([CH2:6][CH2:5]2)[CH:8]=1
Reactant: COc1ccccc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1C1=CC2CCC(C1)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Crude 10a from above (4.124 g) was dissolved in dichloromethane (10 mL) and cooled in an ice-H2O bath. The solution was slowly treated with ice-cold trifluoroacetic acid (10 mL) and stirred at 0° C. for 1 h. The reaction was then concentrated under reduced pressure and the oil obtained re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice-H2O bath and treated slowly with ice-cold 1.0 N NaOH (75 mL). The product was extracted into dichloromethane (2×75 mL) and the pooled extracts washed successively with H2O, saturated NaHCO3 and saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford 1.223 g crude 3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene 10b as a pale amber oil, which was taken to the next step without further purification. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 216.2 [M+H]+, retention time 1.75 min.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>>[CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([Cl:21])=[O:18])=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Product: O=C(Cl)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2

Procedure:
A solution of the above carboxylic acid derivative (2.38 g; 9.64 mmol) in thionyl chloride (10 ml) was heated under reflux for 1.5 h. The excess thionyl chloride was evaporated under reduced pressure to giving (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one-7-carboxylic acid chloride (2.56 g) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][NH:21][CH3:22]>O1CCOCC1.O1CCCC1>[CH3:20][N:21]([CH3:22])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 2-nitro-benzenesulfonyl chloride (15 g, 0.068 mol) in 1,4-dioxane (100 mL) was added sodium carbonate (10.76 g, 0.1015 mol) and 2.000 M of dimethylamine in tetrahydrofuran (40.61 mL) at room temperature and the reaction mixture was stirred for 4 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous layer was extracted once with dichloromethane. The combined organic extracts were dried (MgSO4), concentrated, and the solid residue was recrystallized from MeOH to afford N,N-dimethyl-2-nitro-benzenesulfonamide (14.7 g, 94%) as a white solid. LC/MS (ESI+): 230.92 (M+H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([CH3:48])=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: Cc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (d, J=8.34 Hz, 1 H), 7.84 (d, J=7.58 Hz, 1 H), 7.72-7.60 (m, 1 H), 7.49-7.35 (m, 3 H), 7.09 (ddd, J=8.21, 5.18, 3.03 Hz, 1 H), 6.52 (t, J=5.43 Hz, 1 H), 6.22 (s, 1 H), 5.06 (brs, 2 H), 4.45 (d, J=6.06 Hz, 3 H), 4.38 (d, J=6.06 Hz, 3 H), 3.61 (t, J=4.80 Hz, 2 H), 3.56 (d, J=5.31 Hz, 2 H), 2.31 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:24])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Yield: 76 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (52 mg, 76%) which was obtained as an off white solid. MS: m/e=448.3 [M+H]+.