Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O1CCCC1.O.O.[OH-].[Li+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol;) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1O
Yield: 80 %

Procedure:
A solution of 15 gm (0.1 mole) of 2-hydroxyphenylacetic acid in 500 ml methanol and 2 ml concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours, and the sieves were exchanged at 24-hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 ml toluene and extracted with 3×100 ml portions of water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 13 gm (80% yield) of a yellow oil. The NMR spectrum was consistent with the assigned structure and this material was used in the next reaction step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:21][NH2:22]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:21][NH2:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 84 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[CH3:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[CH3:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)COc1cccc(C)c1

Procedure:
A mixture of chloroacetone (43.75 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of 3-methylphenol (54 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml). Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give a fraction b.p. 126°-134°/13 mm. Redistillation gave 1-(3-methylphenoxy)-propan-2-one, b.p. 124°-126°/13 mm.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19]Br>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19][O:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2Br)C1
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
Sodium hydride (60% oil dispersion, 0.24 g) was added to a stirred solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (0.935 g) in THF (15 mL) and the mixture was stirred for 5 minutes. 2-Bromo-5-fluorobenzyl bromide (1.608 g) was added and stirring was continued for 20 hours. The resultant suspension was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl (S)-3-(2-bromo-5-fluorobenzyloxy)-pyrrolidine-1-carboxylate (1.88 g) as a colourless oil.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)#[N:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:11][CH2:12][N:13]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH2:14][CH2:15]1)#[N:9]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)C4CC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Cyclopropanesulfonyl chloride (66 μl) was added to a suspension of N-[6-(4-cyanopiperidine-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) described in Reference Example 169 and potassium carbonate (207 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 5.5 hours. Water was added to the reaction solution and the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (242 mg) as a white solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11].[C:14]1(O)([CH3:23])[CH2:19][CH2:18][CH:17]([C:20]([CH3:22])=[CH2:21])[CH:16]=[CH:15]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[C:9]2[CH:18]3[CH2:19][C:14]([CH3:23])=[CH:15][CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[O:11][C:10]=2[CH:12]=1
Reactant: Oc1cc(O)cc(C2SCCS2)c1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C

Procedure:
In the third step of the process 5-(1,3-dithiolan-2-yl)resorcinol (V) is reacted with p-mentha-2,8-dien-1-ol having the formula ##STR10## in a suitable liquid reaction medium such as benzene or methylene chloride in the presence of an acid, such as p-toluenesulfonic acid, to induce the condensation. The procedures for this type of reaction are disclosed in Helv. Chim. Acta, 52, 1102 (1969). An elevated temperature, such as the reflux temperature, promotes the reaction and brings it to completion in less than one hour. The desired 3-(1,3-dithiolan-2-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) is then obtained from the reaction mixture, and purified, using routine operations.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1)([OH:33])[CH2:28][CH2:27][CH2:26]2
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2(O)c1ccc(OCCN2CCCC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine (7.0 g, 26 mmol) in dry THF (50 mL) at -78° C. was added n-BuLi (2.5 M in hexanes, 12.4 mL, 31.0 mmol) dropwise. After 30 min, 6-methoxy-1-tetralone (4.55 g, 25.8 mmol) in dry THF was added. After stirring for 15 min at -78° C., the reaction was allowed to warm to room temperature. After 30 min, the reaction was poured into aq NaHCO3 (satd). The aqueous layer was extracted with EtOAc (2×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3 :MeOH, 95:5) provided the alcohol (4.23 g, 44%) as a white solid. 1H NMR (250 MHz, CDCl3): δ8.07 (d, J=2.5 Hz, 1H), 7.49 (dd, J=2.5, 8.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.73 (m, 3H), 4.45 (t, J=5.7 Hz, 2H), 3.79 (s, 3H), 2.92 (t, J=5.7 Hz, 2H), 2.76 (m, 2H), 2.67 (m, 4H), 2.11 (s, 1H), 2.08 (m, 3H), 1.82 (m, 5H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.Cl.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1N(c2ccccc2)CCN1C1CCNCC1
Yield: 93.6 %

Procedure:
11.1 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone are dissolved in 85 ml of methanol, 34 ml of water and 3.2 ml of hydrochloric acid (chemically pure), and, with the addition of 1.2 g of a 5% palladium on charcoal catalyst, hydrogenated at room temperature and under normal pressure. The calculated amount of hydrogen has been taken up after approx. 15 hours. The reaction mixture is filtered to remove the catalyst and concentrated in a water jet vacuum. The crystalline residue is treated with 2N sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are dried over sodium sulphate and concentrated in a water jet vacuum to yield 7.6 g of 1-(4-piperidinyl)-3-phenyl-2-imidazolidinone as a colourless oil which crystallises on standing; melting point 123°-124° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=C([N:42]2[CH:46]=[CH:45][CH:44]=[CH:43]2)C=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: BrCc1cccc(-n2cccc2)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(-n3cccc3)c2)c1=O

Procedure:
Title compound 22 was prepared by the methods used in the preparation of compound 17, except that 1-(3-bromomethyl-phenyl)-1H-pyrrole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.59 (d, J=7.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.36 (m, 4H), 7.21 (t, J=7.6 Hz, 2H), 7.02 (t, J=2.1 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H), 5.42 (s, 1H), 5.11-5.20 (ABq, J=44.7, 15.9 Hz, 2H), 5.06 (s, 2H), 3.36 (m, 2H), 2.98 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.73-1.58 (m, 2H). MS (ES) [m+H] calc'd for C28H29N6O2, 481.2. found 481.2.
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[NH:22]([CH3:24])[CH3:23]>C(Cl)Cl.CCO>[CH3:23][N:22]([CH3:24])[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CNC
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CC(c1cccc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (40 mg, 97.3 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with Me2NH (174 μL of a 5.6 M solution in EtOH, 973 μmol) at rt for 1 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 30-60% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (10.6 mg, 11% over two steps). MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1oc(N)nc1C
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)=O)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 g (11.8 mmol) ethyl 2-amino-4-methyl-oxazole-5-carboxylate in 50 ml DCM are added 6.1 ml (35.3 mmol) DIPEA. To this mixture 0.92 ml (12.9 mmol) acetyl chloride are added and the reaction mixture is stirred at r.t. for 2 h. The mixture is diluted with further DCM and washed with water. The organic layer is separated, dried and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([OH:27])=O)=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C([O:41][C:42](=[O:46])[CH2:43][NH:44][CH3:45])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:33])([CH3:1])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([N:44]([CH2:43][C:42]([OH:46])=[O:41])[CH3:45])=[O:27])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)CC(=O)O)cc2c1
Yield: 73.1 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (720 mg, 1.60 mmol) in CH2Cl2 (10 mL) and DMAP (586 mg, 4.80 mmol) and EDC (460 mg, 2.40 mmol) are reacted with sarcosine ethyl ester hydrochloride (368 mg, 2.40 mmol) and the intermediate ester is hydrolyzed analogous to Example 7 to yield title compound (610 mg, 73%). MS (ES) m/e: 520.3 (M−1), 522.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:11])CO)=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([F:21])[CH:17]=[CH:16][CH:15]=3)[CH:3]=1.[O-]S([O-])=O.[Na+].[Na+].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([F:21])[CH:17]=[CH:16][CH:15]=3)[C:5]([CH:8]=[O:11])=[CH:6][N:7]=1
Reactant: OCC(O)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 1-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)ethane-1,2-diol (1.9 g, 6.21 mmol) in THF—H2O (26 mL-13 mL), NaIO4 (1.94 g, 9.31 mmol) was added, the reaction mixture was stirred at room temperature for 2 hours. Then Na2SO3 and water were added and the mixture was stirred at room temperature for 30 min. The mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (DCM:MeOH=20:1) to afford the desired product of 6-chloro-4-(4-fluoro-1H-indol-2-yl)nicotinaldehyde (1.4 g, yield: 82.4%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.48 (s, 1H), 7.79 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.17˜7.25 (m, 1H), 6.95 (s, 1H), 6.79 (dd, J=8.0, 10.0 Hz, 1H), 6.70 (s, 1H). MS (M+H)+: 275/277.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH2:10][CH:11]1[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][CH2:10][CH:11]2[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CN1CC(CO)CC1=O
Reactant: Brc1ccc(Br)nc1
Product: CN1CC(COc2ccc(Br)cn2)CC1=O

Procedure:
Prepared from 2,5-dibromopyridine and 4-hydroxymethyl-1-methylpyrrolidine-2-one by the method of Example 10 (b).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:24].C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[CH3:34])=[C:3]([CH3:24])[CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Yield: 65.9 %

Procedure:
A solution of 0.83 g of 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c](1,4]benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloride in 50 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, the organic layer dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.75 g of a solid which is crystallized from methylene chloride-hexane to give 0.61 g of the desired product, m.p. 125-130° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.S(Cl)(Cl)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([NH:21][C:6]([C:5]1[S:1][C:2]2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]=2[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc2c(s1)CCCC2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1cc2c(s1)CCCC2
Yield: 88.9 %

Procedure:
A mixture of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (500 g, 2.75 mol, 1.0 equiv) and thionyl chloride (655 g, 5.5 mol, 2.0 equiv) was boiled under reflux for 3 h. Excess thionyl chloride was removed by distillation under reduced pressure. The residue was taken up in dichloromethane (1.0 L) and a solution of tert-butylamine (402 g, 5.5 mol, 2.0 equiv) in dichloromethane (500 mL) was added with stirring while the temperature of the mixture was kept below 10° C. The resulting solution was stirred at 25° C. for 16 h. Most of the solvent was removed under reduced pressure. The residue was chilled in an ice-bath and 2M KOH solution was introduced slowly to adjust the pH to 11 with stirring. The suspension was filtered and the solid was collected, washed three times with water, and dried in vacuo to afford 117a as a white solid (580 g, 80%, over two steps). MS: [M+H]+ 238. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 5.77 (s, 1H), 2.65 (t, J=6.0 Hz, 1H), 2.47 (t, J=6.0 Hz, 1H), 1.74-1.70 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+]>CC(O)C>[NH2:1][C:2]1[C:3]([SH:20])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: [S-2]
Reactant: Nc1nc(Cl)c(Cl)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(Cl)c(Cl)nc1S
Yield: 58 %

Procedure:
A mixture of 19.9 g. (0.1 mol.) of aminotrichloropyrazine, 25.2 g. (0.105 mol.) of sodium sulfide nonahydrate in 500 ml. of 2-propanol was heated to boiling under reflux for 5 hours. After cooling, the reaction mixture was filtered. The filtrate was neutralized with hydrochloric acid and filtered. The solid was washed with water and dried to give 11.4 g. (58% yield) of product.