Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]([CH3:21])[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])(=O)=O)=CC=1.[CH2:22]([N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1)=[O:31])[CH:23]=[CH2:24].C(=O)([O-])O.[Na+].S([O-])(O)(=O)=O.[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:39]([C:35]1[CH:34]=[C:33]([NH:32][C:30]([C:26]2[N:25]([CH2:22]/[CH:23]=[CH:24]/[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:11][C@@H:12]([CH3:21])[C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])[CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:31])[CH:38]=[CH:37][CH:36]=1)[CH3:40]
Reactant: C=CCn1cccc1C(=O)Nc1cccc(CC)c1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCOCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cccc(NC(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 173.3 %

Procedure:
A mixture of (1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonate (310 mg, 0.858 mmol), 1-allyl-N-(3-ethylphenyl)-1H-pyrrole-2-carboxamide (210 mg, 0.826 mmol), palladium acetate (10 mg, 0.045 mmol), sodium hydrogencarbonate (140 mg, 1.66 mmol) and benzyltriethylammonium chloride (190 mg, 0.834 mmol) in dimethylformamide (5 ml) was stirred for 3 hours at 50° C. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene(2/1). The organic layer was washed with water, an aqueous sodium thiosulfate solution and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give N-(3-ethylphenyl)-1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrole-2-carboxamide (349 mg, 83%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([C:20](=O)[CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[O:24])[CH:19]=1)(=[O:13])=[O:12])(C(C)(C)C)(C)C.[Si](OCCS(C1C(OCCC)=C(OC)C=C([C@@H](O)CCC(=O)C2C=C(OC)C(OC)=C(OC)C=2)C=1)(=O)=O)(C(C)(C)C)(C)C.[BH4-].[Na+].C(O)(C(F)(F)F)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)(Cl)Cl.CO>[OH:8][CH2:9][CH2:10][S:11]([C:14]1[C:15]([O:40][CH2:41][CH2:42][CH3:43])=[C:16]([O:38][CH3:39])[CH:17]=[C:18]([CH:20]2[CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[O:24]2)[CH:19]=1)(=[O:13])=[O:12]
Reactant: CCCOc1c(OC)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCOc1c(OC)cc([C@@H](O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCOc1c(OC)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO

Procedure:
1-(5-(2-t-butyldimethylsilyloxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl) butane-1,4-dione from step A is stereospecifically reduced with (S)-BINAL-H (J. Am. Chem. Soc. 1984, 106, 6709) to 1-(5-(2-t-butyldimethylsilyloxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl)-4-oxo-4-(3,4,5-trimethoxyphenyl)-(1S)-butanol (step A'). This compound is reduced (NaBH4, THF, MeOH), cyclized (TFA, CHCl3), desilylated (n-Bu4NF, THF), and purified by chromatography on silica gel using procedures similar to those in step D to give (-)-(2S,5S)-2-(5-(2-hydroxyethylsulfonyl)-4-n-propoxy-3-methoxyphenyl -5-(3,4,5-trimethoxyphenyl)tetrahydrofuran.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:12][C:13]3[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=[CH:21][C:22]=3[N:23]=2)=[N:2]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1
Temperature: 145 °C
Yield: 21.4 %

Procedure:
A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg of methyl 3,4-diaminobenzoate in 10 ml of nitrobenzene is maintained at a temperature in the region of 145° C. for 3 hours and 45 minutes. After cooling to a temperature in the region of 20° C., the reaction mixture is purified on SPE (5 g of SCX phase, processing and washing with methanol, extraction with a 2N ammoniacal methanol solution). The ammoniacal solution collected during the detachment is then concentrated under reduced pressure at a temperature in the region of 40° C. 198.3 mg of an orange lacquer are obtained and are purified by preparative LC-MS. 42.7 mg of methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate are thus obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:13]=[C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:15]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([OH:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:19]=[CH:18][C:16]=2[N:17]=1>>[CH3:1][C:2]1[N:6]([C:12]2[N:13]=[C:14]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]3[N:21]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]([OH:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
Following General Procedure C, 2-methylbenzimidazole and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 101. LCMS (MH+)=502.3. 1H-NMR (DMSO-d6): δ 8.20 (m, 2H), 7.89 (m, 1H), 7.62 (m, 1H), 7.27 (m, 2H), 4.56 (s, 4H), 4.08 (s, 1H), 3.84 (m, 4H), 3.73 (s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 1.98 (m, 2H), 1.67 (m, 2H), 1.29 (m, 2H), 1.18 (m, 1H), 1.04 (s, 6H)
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:11][N:12]3CCC#N)=[CH:7][C:6]=2[F:25])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][NH:12]3)=[CH:7][C:6]=2[F:25])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c2nc(N3CCC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 7D in THF (400 mL) and methanol (200 mL) at reflux was treated with 1M LiOH (200 mL), stirred for an 3 hours then cooled, concentrated to half volume, acidified with 10% citric acid, and filtered.
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=O)[C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:35][CH:36]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc(CCc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(CCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 32.6 g of 1,2-bis(4-(4-nitrobenzoyl)phenyl)ethane and 200 milliliters of dichloromethane were introduced. 42.0 g of trifluoromethane sulfonic acid was added dropwise for 15 minutes. Subsequently, a solution of 40.7 g of triethylsilane in 50 milliliters of dichloromethane was added dropwise for 1 hour. After the end of the dropwise addition, stirring was carried out for 18 hours with warming to room temperature. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was neutralized with an aqueous solution of sodium carbonate and washed with water. After removing dichloromethane by a rotary evaporator, 27.6 g of 1,2-bis(4-(4-nitrobenzyl)phenyl)ethane was obtained as crystals by recrystallizing from a toluene solvent.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH-].[Na+:15]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:15].[Na+:15].[Na+:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A citric acid process stream (about 50% by weight citric acid) was neutralized to pH 8 with a 50% sodium hydroxide solution and then concentrated. 50 ml of concentrated solution was poured into an erlenmeyer flask with stirrer bar. The solution was stirred until it became turbid. At this point, 10 g of sodium hydroxide pellets were added as the crystallizing base. The sodium salt of citric acid started to crystallize rapidly. The mixture was stirred for 2 hours and gradually cooled to room temperature. The mixture was poured into a basket centrifuge and the crystals separated from the mother liquor and collected. The recovery was 92% and the impurities such as carbonizables and color were reduced by more than 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[CH:20]=[C:19]([N:21](C(OC(C)(C)C)=O)[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:33][CH3:34])[C:8]=2[C:7]1=[O:35].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:33][CH3:34])[C:8]=2[C:7]1=[O:35]
Reactant: COc1c2n(c3c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2n(c3c(NS(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-N-methanesulfonyl-amino)-8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (90 mg, 0.15 mmol) and trifluoroacetic acid (2 mL) in anhydrous dichloromethane (3 mL) was stirred for 3 hours. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]3[NH:13][C:26]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][N:18]=[CH:19]5)=[CH:27][C:28](=[O:29])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2cccc(Cl)c2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3cccc(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.52 mmol) in n-BuOH (1 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (280 mg, 1.00 mmol) and TsOH (5 mg, 0.03 mmol), and the reaction mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford 2-(3-chlorophenyl)-5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (75 mg, 34%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].Cl.[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>CS(C)=O>[N+:11]([C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:23][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:13])=[O:12]
Reactant: NCCc1ccccc1
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
A mixture comprising 3-methoxy-4-nitrobenzonitrile (1 g, 5.6 mmol), phenethylamine hydrochloride (1.8 g, 11.2 mmol), 50% sodium hydroxide (0.9 g, 11.2 mmol) and DMSO (3 mL) was heated at 100° C. for 3.5 hours, cooled and poured into a solution of 1N hydrochloric acid (200 mL, 0° C.). The mixture was stirred for 20 minutes to give a precipitate. The precipitate was collected and recrystallized from hot ethanol to provide 4-nitro-3-phenethylaminobenzonitrile (0.78 g, 2.9 mmol) as orange crystals. MS (CI), Calculated for C15H13N3O2, 267.3, Found (MH+): 282. A mixture comprising 4-nitro-3-phenethylaminobenzonitrile (0.75 g, 2.8 mmol), palladium on carbon (100 mg) and 1:1 methanol/THF (100 mL) was hydrogenated under 1 atm for 3 hours, filtered and concentrated under reduced pressure to provide 4-amino-3-phenethylaminobenzonitrile (0.68 g, 2.8 mmol) as a tan solid.
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Yield: 16.1 %

Procedure:
2-Methylsulphinyl-3-nitro-4-phenylpyrrole (2.0 g, 0.008 mol) was partially dissolved in ethanol (150 ml) and a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g, 0.008 mol) in a little ethanol was added to it. The mixture was refluxed for seven days, after which the mixture was stripped and chromatographed on a silica gel column, collecting the required product by elution with ethyl acetate. The crude solid was recrystallised from 2-propanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-phenylpyrrole (0.46 g), m.p. 182°-184°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1cscc1OC
Reactant: CCCCCC[C@H](O)CO
Product: CCCCCCC1COc2cscc2O1

Procedure:
Chiral 2-n-hexyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with (S)-1,2-octanediol and purified to a purity of 99.69% as described in INVENTION EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited a specific rotation of −100° at 25° C. and 436 nm in hexane.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][CH2:1][C:2]#[CH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCCCOCc1ccccc1
Temperature: 40 °C
Reaction time: 0.54 h
Yield: 124.1 %

Procedure:
To a 1:1 mixture of propargyl alcohol (100 mL, 1.72 mol) and anhydrous THF (100 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 14.0 g, 0.35 mol) under nitrogen, portionwise, over 30-35 min. An second reaction mixture was prepared in essentially the same manner. Both reaction mixtures were heated at 40° C. for 2 h and then cooled to room temperature. 4-Benzyloxy-1-bromobutane (90%, 35.0 g, 0.137 mol) was added to each reaction mixture. The resulting solutions were heated at 40° C. for 22 h and then quenched with water (˜5 mL), combined and concentrated in vacuo. The resulting crude product was then partitioned between dichloromethane (2×300 mL) and water (200 mL). The organic phases were removed, washed with saturated brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title intermediate (67 g) as a yellow oil. This oil was then chromatographed on a silica gel column (˜8 kg, 230-400 mesh, flash under 10 psi nitrogen pressure) eluting with dichloromethane (Rf=0.45, dichloromethane). The appropriate fractions were combined and concentrated to give the title intermediate as a clear oil (37.2 g, 0.17 mol, 62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NCC#CCO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC(=O)NCC#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
4-[(tert.-butoxycarbonyl)amino]butanoic acid (5.20 g, 25.6 mmol, prepared in analogy to Houssin et al., (1988) Synthesis 3, 259-261) was dissolved in anhydrous tetrahydrofuran (20 mL), carbonyldimidazole (CDI) (4.56 g, 28.1 mmol) was added and the resulting clear solution was stirred at room temperature for 2 h. Then, the primary amine 11 (3.11 g 25.6 mmol) and trietylamine (7.10 mL, 50.9 mmol) were added and stirring was continued at room temperature for 2 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 40 g, chloroform/ethylacetate 1:1) to give compound 12 (3.59 g, 52%) as a light yellow oil (Rf 0.3, chloroform/ethyl acetate 1:1).
Reaction SMILES: C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC(=O)N[C@@H](C)CO)(C)(C)C.C(OC([C:36]1[N:37]([CH2:49][CH:50]([NH:52][C:53](OC(C)(C)C)=O)[CH3:51])[N:38]=[C:39]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:51][C@H:50]1[CH2:49][N:37]2[N:38]=[C:39]([CH2:41][O:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:40]=[C:36]2[CH2:53][NH:52]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Product: C[C@H]1Cn2nc(COc3ccccc3)cc2CN1

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and (1S)-2-hydroxy-1-methyl-ethyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1.Cl.C(OCC)(=O)C>C1COCC1.CO>[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
1N Aqueous sodium hydroxide solution (8 ml) was added to a mixed solution of methyl 4-(4-biphenylylcarbonylamino)benzoate (1.998 g) in THF (60 ml) and methanol (20 ml), which was stirred at room temperature for 18 hours. 1N Hydrochloric acid (10 ml) was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystals were washed with diethyl ether to give the titled compound (1.760 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([O:27][CH:28]([CH3:33])[CH2:29][C:30](Cl)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:30](=[O:31])[CH2:29][CH:28]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:33])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CC(=O)Cl)OCc1ccccc1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: CC(CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)OCc1ccccc1

Procedure:
The titled compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 3-benzyloxybutyryl chloride (Eberlein, T. H. et al., J. Org. Chem. 1992, 57, 3479).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:30]([NH:29][C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])=[O:31])=[CH:10][C:9]=2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC1
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 4-(2-(azetidin-1-yl)ethoxy)-3-(1-methyl-1H-pyrazol-5-yl)benzenamine (40.1 mg, 0.147 mmol) in CH2Cl2 (2 mL) was added 2,4-difluorophenyl isocyanate (18 μL, 0.152 mmol) and stirred for two hours. The crude reaction mixture was purified by SiO2 column chromatography (Eluent: methanol/CH2Cl2=1/6) to afford the title compound (50.4 mg, 80%). LCMS m/z (%)=428 (MH+, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (bs, 1H), 8.47 (bs, 1H), 8.09-7.98 (m, 1H), 7.45-7.39 (m, 2H), 7.36 (d, J=2.71 Hz, 1H), 7.34-7.26 (m, 1H), 7.06 (d, J=8.94 Hz, 1H), 7.06-6.98 (m, 1H), 6.23 (d, J=1.85 Hz, 1H), 3.89 (t, J=5.49 Hz, 2H), 3.67 (s, 3H), 2.98 (t, J=6.92 Hz, 4H), 2.60 (t, J=5.47 Hz, 2H), 1.86 (quintet, J=6.99 Hz, 2H).