Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:16])[CH:14]=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[C:1]([C:5]1[C:6]2[O:12][C:14](=[O:15])[CH:13]([OH:16])[C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1cc(Cl)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(Cl)cc2c1OC(=O)C2O
Reaction time: 18 h

Procedure:
2.8 g of 2-tert-butyl-4-chlorophenol [J. Amer. Chem. Soc. 78, 4604 (1956)] are heated under reflux with 2.45 g of 50% by weight aqueous glyoxylic acid and 50 mg of p-toluenesulfonic acid in 20 ml of 1,2-dichloroethane for 3¼ hours. A further 2.45 g of 50% by weight aqueous glyoxylic acid are then added and boiling is continued for 18 hours. The reaction mixture is then washed with water, dried over MgSO4 and concentrated by evaporation using a rotary evaporator. Crystallisation of the residue from hexane yields 1.15 g of 7-tert-butyl-5-chloro-3-hydroxy-3H-benzofuran-2-one (melting point : 423-427 K). 1.1 g of that compound are placed in 5 ml of toluene with 1 ml of thionyl chloride and the reaction mixture is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at 373 K for a further hour. Approximately 5 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 13 ml of toluene and, at room temperature, 0.6 ml of triethylamine is added dropwise thereto. The thick, red reaction mixture is then heated to reflux temperature and boiled for 45 min. After cooling to room temperature, the isoxindigo which has precipitated is filtered off, freed of triethylamine hydrochloride by washing with water and methanol and dried, yielding 0.47 g (46% of the theoretical yield) of 7,7′-di-tert-butyl-5,5′-dichloro-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIXa).
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC
Solvent: c1ccncc1
Product: CCCCCC(C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Temperature: 0 °C

Procedure:
A solution of the compound of formula I, methyl trans,cis- 7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate (5 g), described in Example 161, in 50 ml of pyridine and 50 ml of acetic anhydride is stirred at room temperature for 4 hr. The solution is diluted with ice-water and extracted with ether. The ether is washed with 10% H2SO4, water 10% Na2CO3 and water, dried (Na2SO4) and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=C)[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.C[OH:14].ClCCl>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:14])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: C=Cc1nc(Cl)nc(Cl)c1OC
Reactant: CO
Solvent: ClCCl
Product: COc1c(Cl)nc(Cl)nc1C=O

Procedure:
A solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (6.64 g, 32.5 mmol, prepared by Example 2), in methanol:dichloromethane (1:4, 300 mL), was cooled to −78° C. in a dry ice/acetone bath. Ozone was bubbled into the reaction until the starting material was no longer present according to thin layer chromatography (TLC). Dimethyl sulfide (6 mL) was added. The mixture was concentrated on a rotary evaporator at 0° C. to remove the dichloromethane. This provided an unpurified material comprising the title compound. The title compound was not isolated from the unpurified material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[N:41]([CH:44]([CH3:46])[CH3:45])=[C:42]=[O:43]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:42]([NH:41][CH:44]([CH3:46])[CH3:45])=[O:43])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: CC(C)N=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)NC(C)C)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A stirred solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (Example 190, Step 4, 0.124 g, 0.233 mmol) in THF (2 mL) was treated with 2-isocyanatopropane (Aldrich) (0.046 mL, 0.465 mmol) and the yellow solution was stirred at rt overnight. The mixture was concentrated and the crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-7.5%) to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-isopropylurea (0.1044 g, 72% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.74 (s, 1H); 8.98-9.14 (m, 1H); 8.83 (d, J=7.75 Hz, 1H); 8.35 (d, J=1.75 Hz, 1H); 8.24-8.33 (m, 1H); 7.84 (dd, J=8.77, 1.90 Hz, 1H); 7.35 (s, 1H); 7.20 (t, J=8.33 Hz, 4H); 6.86 (t, J=7.38 Hz, 4H); 6.77 (dd, J=7.75, 4.82 Hz, 1H); 6.65 (d, J=8.77 Hz, 1H); 4.84 (d, J=4.97 Hz, 4H); 4.01-4.18 (m, 1H); 3.80 (d, J=7.31 Hz, 6H); 2.60 (s, 3H); 1.28 (d, J=6.58 Hz, 6H). m/z (ESI, +ve ion) 620.0 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)[CH3:19]>>[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[CH3:19]
Reactant: CCc1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CCc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-ethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O>C(O)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a stirred solution of 2-aminothiazole (5 g, 49.931 mmol) in acetic acid (40 ml) was added ethyl acetoacetate (9.48 ml, 74.843 mmol) at room temperature. The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was cooled to room temperature. The residue obtained after concentration under reduced pressure was basified with saturated NaHCO3 solution and diluted with ethyl acetate (50 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 3.3 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Na].Cl[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]3)=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1>ClCCl>[N:5]1([CH2:4][CH2:3][CH2:2][O:1][C:15]2[CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]4)=[CH:23][CH:24]=3)[CH:18]=[CH:13][N:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OCCCN1CCCCC1
Reactant: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(Cl)c3)cc2)C1
Agent: [Na]
Solvent: ClCCl
Product: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(OCCCN4CCCCC4)c3)cc2)C1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To 1-(3-hydroxypropyl)piperidine (287 mg) are successively added sodium (46 mg) and 2-chloro-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine (345 mg). The mixture is heated overnight, cooled back to room temperature and dissolved in dichloromethane (20 mL). The organic phase is washed with water (20 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified over silica gel (eluent (dichloromethane/methanol from 100/0 to 90/10). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is dissolved in ethanol, oxalic acid (32 mg) is added and the precipitate that appears separated by filtration and dried to give 70 mg of 2-(3-piperidinopropoxy)-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine, dioxalate as a white solid melting at 122° C.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[Br:32][C:33]1[CH:34]=[C:35]([CH:39]2[CH2:42][C:41](=[O:43])[CH2:40]2)[CH:36]=[CH:37][CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([CH:39]2[CH2:40][C:41]([C:2]3[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]4[C:9]([C:16]5[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=5[Cl:23])=[N:10][O:11][C:12]=4[CH:13]4[CH2:14][CH2:15]4)=[CH:4][C:3]=3[Cl:26])([OH:43])[CH2:42]2)[CH:36]=[CH:37][CH:38]=1
Reactant: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Reactant: O=C1CC(c2cccc(Br)c2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2Cl)CC(c2cccc(Br)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of compound 1a (14 g, 29.6 mmol) in dry THF (500 ml) at −78° C. was added dropwise n-BuLi (18.5 mL, 1.6 M in hexane, 29.6 mmol). The mixture was stirred for an additional 1 h at −78° C. and a solution of compound 2a (6.5 g, 28.9 mmol) in dry THF (50 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h and then warmed to rt and quenched with saturated aq. NH4Cl (500 mL). The mixture was extracted with EA (500 mL×2), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by CC (EA/PE=1:5) to give the title compound 2b (6.5 g, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: Cc1cc2ncc(C#N)c(Cl)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(C)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (507 mg, 2.64 mmol) and 60% sodium hydride (105.6 mg, 2.64 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-methylthieno[3,2-b]pyridine-6-carbonitrile (275.3 mg, 1.32 mmol) is added. The reaction mixture is heated at reflux for 6 hours, cooled to room temperature and partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane followed by preparative thin layer chromatography developing with 20% ethyl acetate in dichloromethane, to provide 108 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 213-214° C.; 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 3.85 (s, 3H), 7.20 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H); MS 362.1, 364.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: Nc1cccc(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cccc(C(=O)O)c1

Procedure:
5-[1-(t-Butoxy)formamido]valeric acid is coupled with m-aminobenzoic acid to give m-[5-(1-t-butoxyformamido)valeramido]benzoic acid, m.p. 188° C., and the latter is reacted with 3-amino-3-phenylpropionic acid benzyl ester p-toluenesulphonate to give DL-N-[m-[5-(1-t-butoxyformamido)valeramido]benzoyl]-3-phenyl-β-alanine benzyl ester, MS: 574 (17, M+H).
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:18][C@@H:11]1[CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:1]([CH3:3])=[CH2:2])[CH:8]=2)[C:13](=[O:17])[O:12]1
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: C=C(C)[Mg]Br
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 0.5 molar solution of zinc chloride (1.696 g, 12.44 mmol) in dry THF (16.59 mL) was cooled to 0° C. A solution of isopropenylmagnesium bromide (24.89 mL, 12.44 mmol) was added via syringe. The reaction was stirred at 0° C. for 30 minutes before being cannulated into a sealed tube containing (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.00 g, 8.30 mmol), PdOAc2 (0.093 g, 0.42 mmol), and X—PHOS (0.395 g, 0.830 mmol) in THF (16.6 mL) under N2 atmosphere. The tube was heated to 70° C. overnight. The reaction was then cooled and partitioned between water (100 mL) and EtOAc (220 mL). The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. MPLC purification (10-50% EtOac/Hex) gave (3R)-3-methyl-6-(prop-1-en-2-yl)-3,4-dihydro-1H-isochromen-1-one:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][CH2:47][CH:48]([OH:50])[CH3:49]>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH2:47][CH:48]([OH:50])[CH3:49])[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: CC(O)CN
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(CC(C)O)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 63.1 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (639 mg, 1 mmol) and 1-amino-2-propanol (0.19 g, 2.5 mmol) gave the title compound (409.7 mg, 63%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:42]>C(#N)C>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:46]2[CH2:47][CH2:48][N:43]([CH2:41][CH3:42])[CH2:44][CH2:45]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1CCN(C(=O)c2cc(F)c(NCc3ccc(OC)cc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
To a solution of 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (9.00 g, 30.7 mmol) obtained in Step B in acetonitrile (150 ml), N-ethyldiisopropylamine (16.0 ml, 92.1 mmol), HOBt (4.15 g, 30.7 mmol) and WSCI (5.88 g, 30.7 mmol) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (4.68 ml, 368 mmol) was added, followed by stirring at room temperature for 62 hours. N-Ethyldiisopropylamine (5.35 ml, 30.7 mmol), HOBt (2.07 g, 15.3 mmol) and WSCI (2.94 g, 15.3 mmol) were added at room temperature, followed by stirring for 22 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (300 ml), which was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml). Subsequently, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), to obtain the desired compound as a brown oil (11.8 g, 99%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>O>[CH:11]1([NH:14][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Product: c1nc(NC2CC2)c2cc[nH]c2n1
Yield: 28 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 1.06 g, 6.90 mmol) is dissolved in cyclopropylamine (20, 2.42 mL, 34.5 mmol) and heated to reflux overnight. The reaction mixture is cooled and poured into water, then extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (21, 337 mg). MS (ESI) [M+H+]+=174.9. This is reacted similarly to step 2 of Scheme 4 to provide the desired compound 22.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C([Cl:30])C=C(C(OO)=[O:32])C=1.Cl>C(Cl)Cl.CCOCC>[ClH:30].[CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15]([CH3:16])=[O:32])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1csc(Nc2ncc(S(C)=O)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
3-(Benzyloxy)-N-(4-methylthiazol-2-yl)-5-(methylthio)pyridin-2-amine (prepared according to Example 7; 0.057 g, 0.166 mmol) was placed in CH2Cl2 (5 mL) and cooled to 0° C. MCPBA (0.0398 g, 0.166 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours, then quenched with sodium bisulfite and extracted with CH2Cl2. The organic layer was washed with saturated sodium bicarbonate, dried, filtered, and concentrated. The residue was purified by silica gel (40-80% EtOAc in hexanes) to give the free base. The free base was dissolved in CH2Cl2, and 2M HCl in ether was added. The solution was concentrated to give 3-(benzyloxy)-5-(methylsulfinyl)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.037 g, 56.3% yield). 1H NMR (DMSO-d6) δ 8.18 (d, 1H), 7.81 (d, 1H), 7.62 (m, 2H), 7.43 (m, 2H), 7.37 (m, 1H), 6.83 (s, 1H), 5.39 (d, 2H), 2.82 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z=360.0 (M+H-HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=3)=[C:12]([CH2:14][O:15]C3CCCCO3)[N:13]=2)=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:15][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][C:11]=1[CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=1
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(COc3ccc(C#N)c(C)c3)o2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(CO)c(COc3ccc(C#N)c(C)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
5.96 g 4-[2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-ylmethoxy]-2-methyl-benzonitrile were dissolved in 100 ml methanol. 522 mg p-toluenesulfonic acid monohydrate were added and the reaction mixture stirred at room temperature for one hour. The solvent was removed in vacuo. The residue was dissolved in 150 ml ethyl acetate and washed with 80 ml saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.1 g 4-[4-hydroxymethyl-2-(4-methoxy-phenyl)-oxazol-5-ylmethoxy]-2-methyl-benzonitrile as pale yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:13]([CH2:21][CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[CH3:12].[Na].C(O)C>O>[CH2:21]([N:13]([CH2:11][CH2:12][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[CH3:22]
Reactant: CCN(CCCl)c1cccc(C)c1
Reactant: Sc1nc2ccccc2s1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCN(CCSc1nc2ccccc2s1)c1cccc(C)c1

Procedure:
73.5 Parts of 2-mercapto-benzthiazole and 79.0 parts of N-ethyl-N-(β-chloroethyl)-m-toluidine are successively added to a solution of 10.15 parts of sodium in 200 parts of absolute ethanol and the mixture is heated to the refluxing temperature for 6 hours. After cooling, the mixture is poured into 1,000 parts of water, the pH is adjusted to 9-10 and the oil which has separated out is taken up in chloroform. The chloroform solution is washed with water in the usual manner, dried over calcium chloride and evaporated. 127.2 Parts of crude N-ethyl-N-(β-benzthiazolylmercaptoethyl)-m-toluidine are obtained as an oily residue. 65.6 Parts of this toluidine base are dissolved in 43.8 parts of dimethylformamide, 34 parts of phosphorus oxychloride are added dropwise over the course of about one hour at below 50°, and the mixture is stirred for a further 15 hours, at 60°-65°. It is then allowed to cool to approx. 40° and a total of 150 parts by volume of methanol is added--initially dropwise, and whilst cooling externally to 40°-50° until the exothermic reaction has subsided--7 parts of emulsifier are introduced and the pH value is now adjusted to 7-8 by dropwise addition of approx. 55 parts by volume of concentrated aqueous ammonia whilst cooling with water. A solution of 13.8 parts of malodinitrile in 15 parts of methanol is then added, the reaction mixture is stirred for 2 hours at 55°-60° and after cooling the dyestuff of the formula ##STR17## which has precipitated is filtered off. The product is washed with 150 parts by volume of methanol and then with 750 parts of warm water, and after drying at 70° in a vacuum drying cabinet 70.6 parts of dyestuff (87.5% of theory) of melting point 190°-192° are obtained.