Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][CH:15]=[CH:14]1.O1CCCC1.C[O:25][C:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])=O>C(N(CC)CC)C>[OH:18][C@@H:17]1[CH2:16][CH:15]=[CH:14][C@H:13]1[N:12]1[C:26](=[O:25])[C:28]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]2[C:30]1=[O:31]
Reactant: N[C@@H]1C=CC[C@H]1O
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A 31.3 g. (0.115 M) quantity of dl-trans-3-amino-4-hydroxycyclopentene toluenesulfonate is dissolved in 240 ml. of tetrahydrofuran and 47 ml. (0.46 M) of triethylamine. The resultant stirred solution is cooled to 5° and treated dropwise with 22.8 g. (0.115 M) of o-methoxycarbonylbenzoylchloride. The reaction is then allowed to warm to 25°. After 48 hours the reaction is partitioned between Ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and concentrated in vacuo leaving 29.6 g. of residue. This residue is chromatographed over silica gel 60 eluted with 5 l. of (10-90) and 7.5 l. of (20-80) acetone-methylene chloride. Three hundred ml. fractions are collected. The product is isolated in fractions 25-35, which upon standing crystallizes to yield 14.2 g. of dl-trans-4-hydroxy-3-phthalido-cyclopentene, m.p. 114°-116°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])(CC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:17]Cl>O1CCCC1>[CH3:25][O:24][C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:21]=1[O:22][CH3:23])[CH2:17][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Combine 2-pyrrolidinone (0.39 g, 4.62 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (4.3 mL, 1.3 M in hexane, 5.55 mmol). After 15 minutes, add a solution of 3,4,5-trimethoxybenzyl chloride (1.00 g, 4.62 mmol) in tetrahydrofuran (5 mL). After the addition of 3,4,5-trimethoxybenzyl chloride is complete, heat to reflux. After 12 hours, cool the reaction mixture and partition between water and ethyl acetate. Separate the aqueous layer and extract 4 times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:19]=1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: OCc1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cc(F)cc(-c2cnc3nc(CO)ccn23)c1

Procedure:
3-Bromoimidazo[1,2-α]pyrimidin-7-ylmethanol was coupled with 3′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-fluoro-5′-(7-hydroxymethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow solid: δH (360 MHz, DMSO) 4.71 (2H, d, J 6), 5.81 (1H, t, J 6), 7.31 (1H, d, J 7), 7.63 (1H, d, J 9), 7.74-7.95 (5H, m), 8.10 (1H, d, J 8), 8.14 (1H, s), 9.26 (1H, d, J 7); m/z (ES+) 345 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl.O>[CH3:14][S:15]([O:13][CH2:12][CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a solution of Intermediate 2B (986 mg, 4.54 mmol) in CH2Cl2 (20 mL) was added TEA (1.899 mL, 13.63 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.531 mL, 6.81 mmol) was added dropwise. The reaction was stirred for 45 min at 0° C. then warmed to rt and diluted with water (20 ml) and CH2Cl2 (20 mL). The layers were separated, and the aqueous layer extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate 2C (1.30 g, 97% yield). Intermediate 2C was carried onto the next reaction without further purification. HPLC/MS (Method D) RT=1.10 min, [M-MeSO3H+H]+199.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.C(N(CC)CC)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCOCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a cooled solution of 11 g of 2-(2-aminoethoxy)-ethanol in 75 ml of dichloromethane and excess triethylamine was added dropwise 13 g of dodecanoyl chloride in 25 ml of dichloromethane. After stirring at room temperature for 3 hours the reaction mixture was concentrated and then diluted with 100 ml of ethyl acetate and 100 ml of water. The organic layer was washed with 2×50 ml of water and brine, dried, filtered and concentrated to give 13.7 g of crude product. Recrystallization from ethyl acetate/hexane gave 11.2 g of product, m.p. 62°-64° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH2:22]([O:21][CH2:20][CH2:19][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Yield: 76.3 %

Procedure:
9-(2-Benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (25) (35 g, 9.3 mmol) was dissolved in ethanol (9 mL) and then NaOH (1.56 g) in water (15 mL) was added. The reaction was heated at reflux for 2 h. The reaction was concentrated in vacuo and the residue diluted with water and washed with dichloromethane (2×150 mL). The aqueous layer was added drop wise to 2 N HCl (150 mL) and then extracted into dichloromethane (3×150 mL). The organics were dried and concentrated in vacuo to afford 2.48 g (92%) of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (26) as a yellow solid which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 20.4, 21.8, 26.4, 38.3, 42.9, 68.7, 73.3, 105.7, 108.8, 118.7, 119.3, 102.9, 127.4, 127.6, 128.3, 136.2, 137.1, 137.8, 108.9.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
Palladium hydroxide (20%) (700 mg) was added to a solution of (1R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 29; 7.1 g, 22.6 mmol) in methanol (100 ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 45 psi for 20 minutes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (6.9 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([C:32]#[C:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:30][N:29]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)=[N:30][N:29]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(C#CC2CCCCC2)nn3C2CCCCO2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(CCC2CCCCC2)nn3C2CCCCO2)CC1
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of 4-[3-cyclohexylethynyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.34 g, 0.56 mmol) in methanol (15 ml) was added Pd/C (10%, 12 mg, 0.01 mmol). The reaction mixture was hydrogenated at 4 bar for 18 h, Pd/C (10%, 12 mg, 0.01 mmol) was added and hydrogenation pursued for an additional 8 hours. The reaction mixture was then filtered and concentrated under reduced pressure to yield the title compound (0.33 g, 95%) as a grey solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[O:5])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:31][C@H:30]([CH3:32])OS1(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:30]([CH3:32])[CH2:31][NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 103-105° C., EI-MS: m/e=428.1(M+) and α D 20 = - 40.3 , was prepared in accordance with the general method of example 12b) from 5-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. e) (R)-4,8-Dimethyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:45])[NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1>CN(C)C=O>[CH2:38]([O:37][C:35]([NH:34][C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:7](=[O:13])[C:8]2=[O:12])=[CH:32][CH:31]=1)=[NH:45])=[O:36])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.00 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 0.17 g of sodium hydride (60%, oil) was added to the solution, followed by stirring at 50° C. for 30 minutes. Then, the reaction mixture was cooled to room temperature, after which 1.48 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane was added thereto and the resulting mixture was stirred overnight at the same temperature. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain 1.76 g of 4-[3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18]C(C)(C)C)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])=O)(C)(C)C.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:49]1[CH:57]=[CH:56][C:52]([C:53]([NH2:55])=[S:54])=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[C:53]([C:52]1[CH:56]=[CH:57][C:49]([O:16][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=2[OH:18])=[CH:50][CH:51]=1)(=[S:54])[NH2:55]
Reactant: NC(=S)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(C)(C)C)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(OC(=O)c2cc(N)ccc2O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To the solution of 4- or 5-tert-butoxycarbonylamino-2-hydroxy-benzoic acid (2) (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4-hydroxy-thiobenzamide (3.0 mmol) was added and stirred mechanically for 3 h at 0°C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate (7) was treated with a solution of 40% TFA in CH2Cl2. After 2 h the solvent was removed to obtain compound (8) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl21MeOH (8/2), from which 4- or 5-Amino-2-hydroxy-benzoic acid 4-thiocarbamoyl-phenyl ester (8), compound of Formula XXVII, was obtained (48% yield).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 5-Nitro-isoindole-1,3-dione (177 g, 0.904 mol), 4-fluoro-phenol (128 g, 1.13 mol), K2CO3 (419 g, 3 mol) and DMF (2 l) was refluxed with stirring for 3 h before the mixture was poured into water (12 l) with stirring. The precipitate formed was isolated by vacuum filtration, washed with water (8 l) and dried in vacuo at 70° C. to give the title compound as a tan powder (43.2 g); 1H NMR (CDCl3) δ=7.79 (d, 1 H), 7.57 (br s, 1 H), 7.01 to 7.29 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:15]([S:16]([OH:19])(=[O:17])=[O:18])=[N:20][CH2:21][CH2:10][S:9][CH2:8][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C(SC)S(=O)(=O)[O-]
Reactant: NCCSCc1ncccc1Cl
Solvent: CC#N
Product: O=S(=O)(O)C(=NCCSCc1ncccc1Cl)NCCSCc1ncccc1Cl
Reaction time: 1 h

Procedure:
A solution of 2-(3-chloropyrid-2 ylmethylthio)ethylamine (4.06 g) in dry acetonitrile (200 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stired at 60° for 1 hour and then allowed to cool. The mixture was evaporated to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by microanalysis and nuclear magnetic resonance spectroscopy to the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:29]([Si:32](Cl)([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Reaction time: 0.17 h

Procedure:
To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1901, 560.0 mg, 1.60 mmol, prepared as described in Example 18, Scheme 33) in tetrahydrofuran (28.0 mL) was added sodium hydride (100.0 mg, 60% in mineral oil, 2.50 mmol). After 10 minutes, triisopropylsilyl chloride (0.500 mL, 2.36 mmol) was added to the reaction. After 4 hours, the reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (602, 0.70 g, 86.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:11])[C:9]#[N:10].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:11])[C:9]#[N:10]
Reactant: Cc1ccccc1N(C)C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C#N)c1ccccc1CBr
Yield: 474.4 %

Procedure:
22.6 g (0.155 mol) of N-(2-methylphenyl)-N-methyl-cyanamide are dissolved in 300 ml of carbon tetrachloride, admixed with about 5 g of N-bromosuccinimide and 0.1 g of azodiisobutyronitrile and radiated using a UV lamp (250 W) for 5 hours with stirring. Over this period, more N-bromosuccinimide (a total of 32.9 g (0.185 mol)) is added a little at a time. The temperature increases during the reaction, until the solution boils at reflux. The reaction mixture is cooled and filtered, and the filtrate is concentrated under reduced pressure. 30 g of N-(2-bromomethyl-phenyl)-N-methyl-cyanamide of a content of 40% (HPLC) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31]CC)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([OH:31])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C(=O)O)C1
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (290 mg, 0.607 mmol) was dissolved in 3 ml of MeOH. LiOH hydrate (76 mg, 1.821 mmol) was dissolved in 1 ml of water and added to the reaction mixture and allowed to stir for 4 hours. The MeOH was removed under reduced pressure. The aqueous residue was washed with Et2O and then acidified with 3N HCl to give a white precipitate which was filtered and dried to give 270 mgs (99%) of 3-[2-Carboxy-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white powder.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[CH2:14]2)[N:3]=1.[NH2:25][CH2:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[NH2:31][C:27]1([CH2:26][NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][CH2:18][C:17](=[O:20])[C:16]4[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=4[CH2:14]3)[N:3]=2)[CH2:30][O:29][CH2:28]1
Reactant: NCC1(N)COC1
Reactant: Cc1ccc2nc(N3CCC(=O)c4ccccc4C3)nc(O)c2c1
Product: Cc1ccc2nc(N3CCC(=O)c4ccccc4C3)nc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-(4-hydroxy-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 404, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (s, 1 H), 7.90 (d, 1 H), 7.75 (d, 1 H), 7.65-7.55 (m, 3 H), 7.45 (t, 1 H), 5.40 (s, 2 H), 4.77-7.72 (m, 4 H), 4.40 (s, 2 H), 4.05 (brs, 2 H), 3.35 (t, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)=[O:4].[H-].[Na+].I[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4]
Reactant: COC(=O)c1nc2ccccc2[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 1H-benzoimidazole-2-carboxylic acid methyl ester (18) (177 mg, 1.0 mmol) in dry DMF (5 mL) was added sodium hydride (applied as 60% dispersion in oil, 62 mg, 1.5 mmol)) at 0° C. under N2 atmosphere. After 0.5 h, iodomethane (284 mg, 2.0 mmol) was added slowly. The reaction mixture was stirred at RT for 4 h. The reaction was diluted with brine at 0° C. and extracted with EtOAc (3×20 mL). The combined organics were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated and purified by flash column chromatography to provide the title compound (81) (180 mg, 90% yield) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]2[N:8]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC(=O)N2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
A solution of compound 2 (500 mg, 1.56 mmol) in dry ethanol (10 mL) was treated with Pd—C (˜0.05 g) and purged with hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) overnight (18 h). The mixture was filtered through a celite bed and washed with methanol (3×25 mL). The combined organic fractions were dried under reduced pressure to obtain crude compound 3 (0.5 g, quantitative) as a colourless foam. 1H-NMR (DMSO-d6) δ 1.34 (m, 6H), 1.87-2.22 (m, 10H), 5.00-5.03 (m, 2H), 6.34-6.52 (m, 2H), 6.98 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %): 288.2 (MH+, 100), 203.1 (37).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6]2.[CH3:19][SH:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([S:20][CH3:19])=[C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6]2
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1O
Reactant: CS
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1SC

Procedure:
By treating 25 g. of methyl 6-methoxy-1-hydroxy-2-naphthylacetate with 10 ml. of methylmercaptan as described above for the 1,6-dihydroxy compound, methyl 6-methoxy-1-methylthio-2-naphthylacetate is obtained.