Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][C:25]=4[C:16]=3[C:15]3[C:28](=[O:32])[O:29][C:30](=O)[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([O:33][CH3:34])[CH:11]=2.[NH3:36]>C(O)C>[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][C:25]=4[C:16]=3[C:15]3[C:28](=[O:32])[NH:36][C:30](=[O:29])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([O:33][CH3:34])[CH:11]=2
Reactant: N
Reactant: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)OC4=O)c2c1
Solvent: CCO
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)NC4=O)c2c1

Procedure:
510 mg (1.08 mmol) 12-(3-Dimethylaminopropyl)-6,7,12,13-tetrahydro-3,9-dimethoxy-5,7-dioxoindolo-[2,3-a]furano[3.4-c]carbazole are heated in an autoclave for 24 hours at 140° C. in 40 ml of a saturated solution of ammonia in ethanol. After cooling, the precipitate obtained is filtered off with suction, chromatographed on silica gel with toluene/ethanol (10:1 v/v) and the fraction with the Rf 0.25 in toluene/ethanol (5:1 v/v) is isolated. 12-(3-Dimethylaminopropyl)-6,7,12, 13-tetrahydro-3,9-dimethoxy-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from about 230° C. This compound can also be prepared from the same starting material by reaction with hexamethyldisilazane and methanol in dimethylformamide analogously to the process described in the literature (Tetrahedron Lett., 1990, 31, 5201).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH:23]([NH2:26])([CH3:25])[CH3:24].O>O1CCCC1>[CH:23]([NH:26][C:19](=[O:21])[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH3:22])([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)phenyl]propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.59 g of isopropylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene to obtain 3.30 g of desired N-isopropyl-2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]-propionamide. The yield was 87%, and the melting point of this compound was from 203° to 204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1C(=O)CCC1>[C:20]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:30][CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 125 °C
Yield: 51.6 %

Procedure:
N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 0.9 mmol) and benzoylpiperazine (0.53 g, 3.00 mmol) were dissolved in 15 NMP and heated at 125° C. for 16 hours. The reaction was quenched with 100 ml water after cooling to room temperature. The mixture was extracted with 50 ml acetyl acetate and washed by water (3×20 ml). N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)benzamide (0.20 g, 50%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.06 (s, br, 4H), 3.85 (d, br, 4H), 7.31 (d, J=8.8 Hz, 1H), 7.48 (m, 5H), 7.62 (m, 2H), 7.65 (m, 1H), 7.95 (d, J=7.1 Hz, 2H), 8.06 (dd, J=2.6, 8.8 Hz, 1H), 9.12 (s, 1H), 9.47 (d, J=2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 52.4, 115.9, 119.9, 121.0, 127.3, 127.6, 129.2, 129.7, 130.7, 133.0, 134.2, 134.5, 135.5, 145.9, 146.7, 165.3, 171.2.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(Cn2cncn2)c1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Reactant: Clc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1(c3ccccn3)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (7.3 ml, 2.09M in hexanes) was added dropwise at ambient temperature to a solution of diisopropylamine (2.12 ml) in dry tetrahydrofuran (14 ml). After 15 minutes, the solution was cooled to -23° C. and a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (3 g) in tetrahydrofuran (34 ml) was added. After 30 minutes the mixture was cooled to -78° C., treated with 2-chloropyridine (1.56 ml), stirred for 1 hour then warmed to ambient temperature. The mixture was heated under reflux for 5 minutes, stirred for 16 hours at ambient temperature, then heated under reflux for 30 minutes. The reaction mixture was poured onto water and extracted with ethyl acetate. The extracts were dried and concentrated and the residual orange oil heated at 90° C. at 13.3 mbar to remove excess 2-chloropyridine. The residue was purified by flash chromatography over silica gel using a 5:1 mixture of light petroleum and triethylamine as eluant to give 7-methoxy-1-[1-(2-pyridyl)cyclobutyl]-3,4-dihydroisoquinoline as a solid (0.58 g).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CC1

Procedure:
The title compound, white solid (31 mg, 49%), MS (ISP) m/z=399.3 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) cyclopropane-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21].Cl.N>CCOCC.C1C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:20]([C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=2)[OH:21])[CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Cc1ccnc(Br)c1C
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1cc(C(O)c2nccc(C)c2C)cc(OC)c1OC
Temperature: -40 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
40 g of 2-bromo-3,4-dimethylpyridine dissolved in 50 ml of anhydrous ether are slowly added, with agitation and under a nitrogen atmosphere, to 300 ml of a 0.9 M solution of butyl-lithium in ether cooled to -40° C. The resulting mixture is agitated for 2 hours at this temperature, and 50 g of 3,4,5-trimethoxybenzaldehyde dissolved in 200 ml of anhydrous benzene are added, and the mixture kept at a temperature below -25° C. Agitation is performed for 1 hour at -15° C, and the reaction is continued until ambient temperature is reached. The mixture is poured on to ice and dilute hydrochloric acid, the acid layer is made alkaline with a current of ammonia, while cooling externally with ice. The precipitate is collected by filtration, supplying 62.6 g of (II). Yield 96%. An analysis sample is crystallized from alcohol (m.p. = 104-6° C). Analysis: C17H21NO4. Calculated: C = 67.31, H = 6.98, N = 4.62. Found: C = 67.23, H = 7.33, N = 4.57.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:9]1[NH:10][NH:11][C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([Cl:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[ClH:27].[ClH:1].[CH2:3]([C:9]1[NH:10][N:11]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=2)[C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCC1=Nc2cccnc2NN1
Agent: Cl
Product: CCCCCCC1=Nc2cccnc2N(C(=O)c2cccnc2)N1

Procedure:
12 g (0.04 mole) of 3-n-hexyl-1,2-dihydropyrido-[3,2-e]-as-triazine dihydrochloride are boiled with an excess of nicotinic chloride. The reaction mixture is cooled and the separated product is filtered off.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:20]#[N:21])=[O:16])=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH:5]=[C:4]([F:31])[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[C:20]([C:19]1[CH:18]=[C:17]([CH:24]=[C:23]([CH3:25])[CH:22]=1)[C:15]([C:14]1[N:9]([CH2:8][C:6]2[CH:5]=[C:4]([F:31])[N:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=2)[C:10](=[O:30])[N:11]([S:33]([CH3:32])(=[O:35])=[O:34])[C:12](=[O:29])[C:13]=1[CH:26]([CH3:28])[CH3:27])=[O:16])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(N)nc(F)c2)c1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)n(S(C)(=O)=O)c(=O)n2Cc2cc(F)nc(NS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
3-[3-(2-Amino-6-fluoro-pyridin-4-ylmethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (86 mg, 0.204 mmol) was dissolved in 5 mL THF. TEA (0.31 μl, 12 eq.) was added and the reaction was stirred at 0° C. for 10 minutes. MsCl (158 μl, 10 eq.) was added. The reaction was stirred at 0° C. for 40 minutes. The reaction crude was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white powder (89 mg, 75%). LC-MS shows 578.0 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.6 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 4.82 (dd, 2H), 3.63 (s, 3H), 3.56 (s, 3H), 2.43 (s, 3H), 2.22 (m, 1H), 1.22 (dd, 6H).
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH2:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>C(#N)C.O.[OH-].[Na+].O>[N:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccncc1
Reaction time: 8 h

Procedure:
8 g of 4-pyridylmethyl 4-nitrophenyl carbonate and 4.82 g of L-phenylalanine were dissolved in 350 ml of acetonitrile/water 1:1, and about 45 ml of 2N NaOH were added to pH 10. The mixture was stirred overnight and was freed from the acetonitrile in vacuo. The aqueous solution was brought to pH 6, washed three times with diethyl ether, subsequently brought to pH 1 and concentrated to give a solid residue. This was dissolved in water and the solution was extracted intensively with ethyl acetate and then brought to pH 2 and the precipitate which had separated out was filtered off with suction. After drying, the precipitate weighed 7.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:29]=1[NH2:30].Cl.N1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:29]=1[NH:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COc1cc(Nc2ncnc3cc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a suspension of 0.05 g (0.133 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 2 mL of isopropanol is added 0.031 g (0.161 mmol) of 2,4-dichloro-5-methoxyaniline and 0.016 g (0.133 mmol) of pyridine hydrochloride. The mixture is brought to reflux for 2 hours, then allowed to cool to room temperature. A yellow precipitate formed, which is filtered and washed with cold isopropanol. Drying in vacuo provided 0.030 g of (2,4-dichloro-5-methoxyphenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine dihydrochloride as a yellow solid, mp 258-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:20][C:21]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:20][C:21]1[N:28]=[CH:27][C:26]([C:18]2[N:13]3[C:14]([S:15][C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:12]3)=[N:16][CH:17]=2)=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Reactant: CC1(C)OB(c2cnc(N)c(C#N)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N)c(C#N)c4)cnc3s2)cc1OC
Temperature: 110 °C
Yield: 21.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.1 g, 0.258 mmol, 1 eq), 2-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (0.11 g, 0.449 mmol, 1.74 eq), PdCl2(Ph3P)2 (36 mg, 0.052 mmol, 0.2 eq) and Na2CO3 (2 M aqueous solution, 0.5 mL) in dioxane was heated at 110° C. for 2.5 h. The reaction was cooled down to it and solvents were removed under reduced pressure. The residue was treated with water, sonicated and then filtered. The solid was washed with water, Et2O, Et2O/MeOH (9:1), and dried. The residue was purified on silica gel (isolute flash Si II, DCM/MeOH 5 to 10% MeOH and biotage, MeOH/DCM, 0% to 10%) to give the desired product (21 mg, 22%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.68 min, [M+H]+ m/z 379.1; 1H NMR (300 MHz, DMSO) δ 8.91 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.72 (s, 2H), 7.56 (dd, J=8.4, 2.1 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.17 (m, 3H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2oncc2-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(C(=O)c1ccc(Cl)cc1)c1ccncc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.5 g, 79.9 mmol) and 150 mL of a 1N sodium hydroxide solution was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and adjusted to pH 6 with concentrated hydrochloric acid. The precipitates were filtered, washed with water and ethanol, and dried to give 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (20.0 g, quantitative yield). m.p. 225.4-234.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ8.12 (brs, 2H), 7.73-7.59 (m, 5H), 7.30 (d, 3H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0481 (M+H, C14H9N20Cl requires 257.0482).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12](=[O:24])[CH2:11]1.[Cl:25][CH2:26][C:27](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:14][N:13]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:12](=[O:24])[CH2:11]3)[C:27]([CH2:26][Cl:25])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(CN2CC(Nc3ccc(Cl)cc3N)CC2=O)cc1
Reactant: CCOC(CCl)(OCC)OCC
Product: COc1ccc(CN2CC(n3c(CCl)nc4cc(Cl)ccc43)CC2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[(2-amino-4-chlorophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one (1.35 g, 3.91 mmol) and 2-chloro-1,1,1-triethoxyethane (10 mL) was stirred at 80° C. for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (DCM: MeOH=20:1) to afford 4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]-1-(4-methoxybenzyl)pyrrolidin-2-one.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2ncccc2c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1ccc2ncccc2c1
Yield: 45.5 %

Procedure:
To a solution of 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (20 g, 69.4 mmol) in MeOH (100 mL) was added hydrazine monohydrate (3.47 g, 69.4 mmol). The solution was heated at reflux for 3 h, then cooled to it and filtered through celite. The filtrate was concentrated in vacuo. EtOAc then was added to the residue and the resulting solution was filtered and concentrated in vacuo to afford 5 g (41%) of the title compound. LCMS (method B): [MH]+=159, tR=0.93 min.
Reaction SMILES: CC#N.[OH2:4].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl>CC#N>[CH2:7]([CH:6]1[CH2:5][O:4]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCCCCCC
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCC1CO1
Yield: 99 %

Procedure:
Under a flow of F2 (10% in N2) of 20.0 ml min−1 (3.33 mmol h−1) passed through conduit 12, MeCN:H2O (4:1, 4.95 ml) was added to conduit 16 at a rate of 9.90 ml h−1 (110.0 mmol h−1) and dodec-1-ene 24 (0.18 g, 1.07 mmol) (in a 1:1 mixture of DCM:MeCN) was added to conduit 38 at a rate of 9.90 ml h−1. All reaction fluids were collected in pot 22 containing sodium bicarbonate solution 25 (50 ml). The reaction mixture was then added to another 25 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 2-decyloxirane (0.195 g, 1.06 mmol, 99%) as a yellow oil, with no further purification required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 97.4 %

Procedure:
In a 3 gallon autoclave, charge 4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (475 g), ethyl acetate (2.5 L), absolute ethanol (2.5 L) and 10% Pd—C (45 g, w/w) under 35 psi hydrogen at ambient temperature for 5 hours. Filter the crude reaction over Hyflo. Concentrate the filtrate under vacuum to give a light yellow solid (465 g) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([O:32]C)=[O:31])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:34](=[O:36])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([OH:32])=[O:31])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:34](=[O:36])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1Cc1ccccc1
Yield: 45.2 %

Procedure:
A solution of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (16.2 mg, 0.034 mM) and 0.034 mL (0.034 mM) of 1 N NaOH in 3 mL of ethanol was stirred for 16 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 7.1 mg (70%) of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.5-6.8 (m, 14H), 6.65 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.05 (d, 1H, J=8 Hz), 5.55 (s, 2H), 4.35 (s, 2H), and 4.3 (s, 2H). IR (CHCl3, cm−1) 1666, 1616, 1495, 1452, and 1422. MS (ES) m/e 463, 465.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:34][CH2:33][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:26][C:22]=2[CH3:21])=[CH:8][CH:7]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid methyl ester as colorless viscous oil.