Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.CO>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 10 h
Yield: 85.2 %

Procedure:
After 2-amino-4-(4-nitrophenoxy)pyridine (160 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, triethylamine (0.289 ml) and phenyl chloroformate (0.260 ml) were added while stirring in an ice water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and to the resultant residue was added N,N-dimethylformamide (8 ml). 4-(Pyrrolidin-1-ylmethyl)piperidine dihydrochloride (668 mg) and triethylamine (0.772 ml) were added and stirred for 4 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The separated organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) as a pale yellow oil. 4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere, 10% palladium on carbon (147 mg) was added and stirred under a hydrogen atmosphere for 10 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white foam (233.7 mg).
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[CH3:28])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[CH2:2]([C:1]1[NH:18][C:19]2[C:20]([CH:28]=1)=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Yield: 59.9 %

Procedure:
A mixture of 4-(n-hexadecanamido)-3-methylbenzoic acid (6.3 g) and potassium tert-butoxide (25 g) was treated in a similar manner to that described hereinbefore in Example 1 to give 2-(n-pentadecyl)indole-5-carboxylic acid (3.6 g), in the form of a white solid, m.p. 110°-112° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1nnsc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1nnsc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Methyl 5-formyl-1,2,3-thiadiazole-4-carboxylate (460.0 mg, 0.0026 mol) was dissolved in ethanol (40 mL) and sodium tetrahydroborate (50 mg, 0.0013 mol) was added at 0° C. The orange solution was allowed to warm to room temp and was stirred for 30 minutes. The reaction was quenched with acetic acid and then purified by preparative LCMS to give the desired product (340 mg, 73%). MF=C5H6N2O3S; LCMS calculated for C5H7N2O3S (M+H)+: m/z=175.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=1.C(OCC)(=O)C.[I:24]N1C(=O)CCC1=O>>[I:24][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccn2)[nH]1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(-c2ccccn2)nc(C(F)(F)F)c1I
Temperature: 132.5 °C

Procedure:
2-(Pyridin-2-yl)-6-trifluoromethyl-3H-pyrimidin-4-one (15.0 g) was dissolved in DMP (150 ml) and N-iodosuccinimide (33.6 g) was added at room temperature with stirring. The mixture was stirred under heating (130-135° C.) for 6 hr. and then cooled to room temperature. The reaction mixture was added ethyl acetate (150 ml), and then washed with aqueous sodium thiosulfate, water and brine, respectively. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give crude 5-iodo-2-(pyridine-2-yl)-6-trifluoromethyl-3H-pyrimidin-4-one. It was recrystallized from toluene as pale brown needles (10.2 g), mp 186-187° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21]C)[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:24]#[CH:25])[OH:23])[CH3:2].Cl.O>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([C@@H:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:24]#[CH:25])[OH:23])=[CH:16][C:15](=[O:21])[CH2:14][CH2:13]4)[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(C)C4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CC
Agent: Cl
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Yield: 17.9 %

Procedure:
Stir dl-13-ethyl-3-methoxy-17α-ethynyl-17-hydroxy-6-methylgona-2,5(10)-diene (3.5 g) in methanol (90 cc) containing hydrochloric acid (60 cc) and water (4.0 ml) under nitrogen for 1 hour. Isolate the crude product, chromatograph on Florex (150 g) and recrystallize from ethyl acetate-hexane to obtain the title compound (0.60 g), m.p. 148°-151°, λmax. CHCl3 2.55 μ, 3.05 μ, 6.01 μ; λmax. EtOH 240 mμ (ε15,100).
Reaction SMILES: [I:1]Cl.[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[I:1][C:8]1[CH:9]=[CH:10][C:3]([OH:4])=[CH:5][C:6]=1[OH:7]
Reactant: ClI
Reactant: Oc1cccc(O)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(I)c(O)c1
Yield: 50 %

Procedure:
A solution of iodine monochloride (8.2 g, 50.5 mmol) in dry diethyl ether (100 mL) was added drop-wise over 45 minutes to a cold solution (0° C.) of resorcinol (5.5 g, 49.9 mmol) in dry ether (50 mL). After stirring at room temperature for one hour 100 mL of water and 1.0 g of sodium sulfite was added. The organic phase was separated and the aqueous phase was washed with 100 mL of ether, the combine ether phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified using flash chromatography over silica gel using a mixture of CH2Cl2:MeOH (100:1) to provide the title compound in 50% yield. 1HNMR (300 MHz, CDCl3) δ 4.95 (s, 1H), 6.23 (m, 1H), 6.55 (m, 1H), 7.43 (m, 1H). MS (CDI) m/z 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][N:12]([C:15]([C:17]4[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=4[O:25][CH3:26])=[O:16])[CH2:11]3)[O:8][C:4]=2[CH:3]=1.CI.[C:31]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]([CH3:31])[C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]([C:17]4[C:18]([O:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][CH3:24])=[O:16])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(OC)c1C(=O)N1CCC(Nc2nc3ccc(Cl)cc3o2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](N(C)c2nc3ccc(Cl)cc3o2)C1
Temperature: 75 °C
Yield: 46.2 %

Procedure:
A mixture of 20 mg (0.05 mmol) [3-(6-Chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone (example 1), 353 mg (2.48 mmol) methyliodid and 10 mg (0.075 mmol) K2CO3 in 0.5 mL DMF was stirred at 75° C. The mixture was concentrated, water and methanol was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 9.6 mg (461%) of the title compound as light yellow solid. (MH+) 418.1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][C:8]([Si:11]([CH3:12])([CH3:14])[CH3:13])=[CH:7][C:6]=2[CH:5]=[C:4]([NH:15][S:25]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[O:17][CH3:16])(=[O:27])=[O:26])[CH:3]=1
Reactant: C[Si](C)(C)c1cc2cc(N)cc(Br)c2o1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(Br)c2oc([Si](C)(C)C)cc2c1
Yield: 99.4 %

Procedure:
Coupling of the amine (4.5 g, 15.9 mmol) from Step 1 with 2-methoxy-5-methylphenylsulfonyl chloride (3.5 g, 15.9 mmol) in dichloromethane (200 mL) using pyridine as a base (3.2 mL, 40 mmol) required 2.5 hours at ambient temperature. Washing the resulting mixture with water, drying and concentration yielded 7.4 g (100%) of N-(7-bromo-2-trimethylsilanyl-benzofuran-5-yl)-2-methoxy-5-methyl-benzenesulfonamide as a dark orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=1.[CH3:26][O:27]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:17]=[C:18]([O:23][CH3:24])[CH:19]=[C:20]([CH3:22])[C:21]=1[CH:26]=[O:27]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(C)cc(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C=O
Temperature: -78 °C
Yield: 60 %

Procedure:
A mixture of 1 mmol of 3,5-dimethoxy-2-(5-methyl-3-methoxy-phenoxy)-4-methyl-benzoic acid methyl ester and 6 mmol of dichloromethyl methyl ether was taken in 8 mL of dichloromethane. The mixture was cooled to −78° C. under stirring, and then titanium tetrachloride (6 mmol) in dichloromethane (4 ml) was added dropwise over 0.5 h. Upon completion, the reaction mixture was poured into ice-cold water and partitioned. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO4, and the solvent was evaporated by a rotary evaporator. The residue was purified by column chromatography to afford 2-(3-methyl-2-Formyl-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (60%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[NH2:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1COc1cccnc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccccc1COc1cccnc1[N+](=O)[O-]
Yield: 97 %

Procedure:
A solution of 2-nitro-3-(2-phthalimidomethylbenzyloxy)pyridine (2.71 g) and hydrazine hydrate (1.05 g) in ethanol (54 ml) was refluxed for 1.5 hours. After cooling, precipitates were filtered off, and the filtrate was evaporated under reduced pressure. The resultant residue was dissolved in diethyl ether and insoluble materials were filtered off. The solvent was evaporated under reduced pressure to give 3-(2-aminomethylbenzyloxy)-2-nitropyridine (1.75 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:38])[S:9]([CH:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]=[C:18]2[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37])C#N)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]([CH3:38])[S:9]([CH2:12][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:19]=[C:18]2[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)Cc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(CS(=O)(=O)N(C)Cc3ccccc3)cc12
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a stirred solution of N-benzyl-1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide (from step (e), 29 g, 55.1 mmol) in ethanol (200 ml) at ambient temperature was added 2N potassium hydroxide solution (200 ml, 400 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hr. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3×300 ml). The organic extracts where combined and evaporated in vacuo to give a dark brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitle compound (24.67 g, 89%) as a brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:10]=1[O:11][CH3:12])=[O:5])C.[OH-].[Na+].[Na].Cl>C(O)C.O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]([O:11][CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]1
Reactant: CCOC(=O)c1nnn(Cc2ccccc2Cl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1c(C(=O)O)nnn1Cc1ccccc1Cl

Procedure:
3.3 g (11.2 mmol) of 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid ethyl ester are dissolved in 50 ml of warm ethanol and, after the addition of 15 ml of 1N sodium hydroxide solution, heated for 1 hour under reflux. The precipitated sodium salt is dissolved by the addition of 250 ml of water and then acidified with 15 ml of 2N hydrochloric acid. The precipitated product is filtered off with suction and washed with water. In this manner there is obtained 1-(o-chlorobenzyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid having a melting point of 130°-135° (with decarboxylation).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[CH:7][CH:8]=[C:9]([CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:10]=2.[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]3=[CH:7][CH:8]=2)=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Into 20 ml of dichloromethane, 0.57 g (2.5 mmol) of (E) 3-(2-amino-benzo[d]phenyl)-2-methyl-2-propenoic acid and 0.52 g (3.8 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 20 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Further, while the mixture was stirred under cooling with ice, 0.71 g (3.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbon ate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 0.69 g of the aimed product was obtained as a crystal (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[CH:37]1.O>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NS(=O)(=O)c1cn(C)cn1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 18 h

Procedure:
To (1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-amine (1a, 60 mg, 0.14 mmol) 130 μmol) in dichloromethane (6 mL) was added triethylamine (55 μl), followed by 1-methylimidazole-4-sulfonyl chloride (36 mg, 200 μmol) and DMAP (2 mg, 17 μmol). The stirring was continued for 18 hours at room temperature and the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with brine, died over sodium sulphate, the solvent was removed i.vac., and the product purified by chromatography on silica gel.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:12][CH2:13][NH2:14].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH:14][CH2:13][CH2:12][C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH3:7])[CH:10]=1)[CH3:21]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNCCc1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h
Yield: 71 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (300 g) and 3,4-dimethoxyphenethylamine (148 g, 0.818 m) in dimethylformamide (750 ml) under N2 at 110° C. was added dropwise over 30 min bromoacetaldehyde diethylacetal (167.5 g, 0.850 m). During the addition, the temperature was allowed to rise to 130° C., maintained at 125°-130° C. for 1.5 hours, then the solution cooled. At ca 40° C., 70 ml of water were added, the mixture was stirred for 1 hour, then the inorganic salts were removed by filtration and the solvent evaporated. n-Hexane (750 ml) was added, the precipitated solid was filtered and the filtrate evaporated to an oil, 247 g. This material was vacuum-distilled to give three fractions: (1) b.p. 30°-154° C./0.1 mm, 17.0 g; (2) b.p. 154°-157° C./0.1 mm, 171.6 g; (3) b.p. 157°-174° C./0.1 mm, 37.3 g. Fraction (2) contained the product in 71% yield and 86% purity (GLC).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:44][CH2:45][C:46](O)=[O:47])=[CH:36]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]([NH:14][C:12]2[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:37]4[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[NH:35][CH:36]=4)[CH2:10][CH2:9][C:8]=3[C:11]=2[C:25]([NH2:27])=[O:26])=[O:24])=[CH:18][CH:19]=1
Reactant: NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(CCCNC(=O)CCc1c[nH]c3ccccc13)C2
Yield: 38.2 %

Procedure:
To a stirred solution of 6-(3-aminopropyl)-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide (0.14 mmol) in anhydrous THF (1.5) were added triethyl amine (93 μL, 0.66 mmol), 3-indolepropionic acid (31 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (25 mg, 0.16 mmol) and the resultant mixture was stirred at room temperature for 8 h. Upon completion, the solvent was removed in vacuo and the oil was taken up in DCM. The organics were washed with water (×2) and dried (anhydrous Na2SO4) and evaporated to afford the crude product which was purified by flash chromatography Isolera system (SiO2 gel as stationary phase, 12 g HP column, dry loading) using DCM-DCM/MeOH (0%-12% MeOH in DCM) to afford the title compound as a brown solid (31 mg, 37% yield). 1H NMR (300 MHz, MeOH-d4) δ 7.55 (d, J=15.5 Hz, 1H), 7.50-7.43 (m, 2H), 7.34-7.24 (m, 3H), 7.12-6.95 (m, 3H), 3.38 (bs, 2H), 3.17 (t, J=6.7 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.36-2.27 (m, 2H), 1.67-1.54 (m, 2H). LRMS [M+H]579.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)(C)C>[C:1]([NH:9][NH:10][C:13](=[S:14])[NH:12][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CN=C=S
Solvent: CC(C)O
Product: CNC(=S)NNC(=O)c1ccncc1
Temperature: 70 °C
Yield: 93 %

Procedure:
To a gently heated (35° C.) and mechanically stirred suspension of isonicotinohydrazide (435 g) in isopropyl alcohol (6.0 L) was added (methylimino)(thioxo)methane (230 g) in several small portions. After complete addition, the reaction mixture was heated (70° C.) for 6 h with an additional addition of isopropyl alcohol (600 ml) after 30 min. After cooling (ice-bath) the reaction mixture to 17° C., the obtained precipitate was filtered off and washed with isopropyl alcohol (1.0 L). This solid was then air-dried over night to provide 615 g of the title compound as a white powder.