Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:12])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Br)c(C=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(O)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-4,6-dimethoxybenzaldehyde (7.35 g, 30.0 mmol) in dichloromethane (50 mL) was added dropwise boron tribromide (18.75 g, 75.0 mmol) at −78° C. The reaction mixture was stirred at room temperature overnight, poured into ice and extracted with ethyl acetate (80 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/3) on silica gel to give the title compound as a white solid. (5.09 g, Y: 78.2%). 1H NMR (400 MHz, DMSO-d) δ12.18 (s, 1H), 11.33 (s, 1H), 9.98 (s, 1H), 6.71-6.72 (d, J=2.4 Hz, 1H), 6.30-6.31 (d, J=2 Hz, 1H). MS (ESI) m/z=217 [M+H]+.
Reaction SMILES: O.[CH2:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:3][CH3:4].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH2:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: CCCc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: CCCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 288 h

Procedure:
To a stirred mixture of 100 ml of water, 100 ml of ether and 10.0 g of 2-n-propylphenol was added dropwise 11.0 ml of 61% nitric acid and the reaction was carried out with stirring at room temperature for 12 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1 : 1)]to give 3.76 g of 6-n-propyl-2-nitrophenol.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@H:21]2[C@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][CH3:30])[O:22]2)=[C:14]([NH:31][CH2:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:13]=1.C(N(CC)CC)C.CCCCC>CN1CCCC1=O>[OH:26][C@@H:25]1[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][CH3:30])[O:22][C@H:21]1[N:18]1[CH:17]=[N:16][C:15]2[C:19]1=[N:20][C:12]([CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[N:13][C:14]=2[NH:31][CH2:32][CH:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCCCC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNc4ccc(C#N)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 120 °C
Yield: 15.6 %

Procedure:
6-Chloronicotinonitrile (78 mg, 0.56 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1) and triethylamine (57 mg, 0.56 mmol) in N-methyl-2-pyrrolidinone (10 ml). The reaction mixture was heated at 120° C. for 24 hr. The reaction mixture was then partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give material that was still impure and hence re-purified by column chromatography on silica gel eluting with a solvent system of ethyl acetate:methanol (90:10) to give a yellow oil which was treated with pentane to give the title compound (47 mg) as a solid. MS: 594 (MH+).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH:33]5[CH2:35][CH2:34]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl>[CH:33]1([N:28]2[C:26]3[N:27]=[C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)=[CH:16][N:17]=4)[N:23]=[CH:24][C:25]=3[CH:31]=[CH:30][C:29]2=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CC5)c4n3)nc2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=c1ccc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl gas was bubbled through a solution of 4-[6-(8-cyclopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (96 mg, 0.21 mMol) in CH2Cl2 (5 mL) for a few minutes until solid was formed. The mixture was stirred at room temperature for 18 hours and the solid formed was collected by filtration and washed with CH2Cl2 then dried in vacuo to give the desired product 8-cyclopropyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as its hydrochloride salt (83 mg, 85%). mp >300° C. Anal Calc'd for C19H21N7O. 2.1 HCl. 1.5 H2O: C, 48.87; H, 5,63; N, 20.99. Found: C, 49.23; H, 5.53; N, 20.68.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>ClCCl>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3cc(C)ccn3)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3cc(C)ccn3)c2s1
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A stirred solution of 1-[5-Benzyloxy-7-(4-methyl-pyridin-2-yl)-benzothiazol-2-yl]-3-ethyl-urea (100 mg, 0.239 mmol) in anhydrous dichloromethane (2 ml) was treated with methanesulfonic acid (0.25 ml) and kept at ambient temperature for 2 h. The dichloromethane was then evaporated off and the residue treated with water (3 ml). The resultant mixture was extracted with ethyl acetate (3×20 ml) and the aqueous portion basified with sodium hydrogen carbonate. The resultant mixture was extracted with ethyl acetate (3×30 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 1-Ethyl-3-[5-hydroxy-7-(4-methyl-pyridin-2-yl)-benzothiazol-2-yl]-urea (38 mg, 46%) as an off-white solid which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:18]1([CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: C1CNCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Yield: 78.5 %

Procedure:
A mixture of hexahydro-1H-1,4-diazepine (3.44 g, 34.4 mmol) and 1-(chloromethyl)-4-(benzyloxy)benzene (2.0 g, 8.6 mmol) was treated with triethylamine (4.8 ml, 34.4 mmol) in 100 mL tetrahydrofuran and heated at reflux for 4 h. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 2.0 g of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, 2H), 7.39 (dd, 2H), 7.32 (dd, 1H), 7.26 (d, 2H), 6.93 (d, 2H), 5.05 (s, 2H), 3.60 (s, 2H), 2.96 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.65 (m, 2H), 1.75 (m, 2H) ppm.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH3:55][N:56]1[CH:60]=[CH:59][N:58]=[C:57]1[CH2:61][CH2:62][CH:63]=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:63]/[CH2:62][CH2:61][C:57]1[N:56]([CH3:55])[CH:60]=[CH:59][N:58]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1CCC=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(/C=C/CCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl )-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (3.0 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.13 g) and ethanol (45 ml)). Then 3-(1-methylimidazol-2-yl)propionaldehyde (0.787 g) was added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (30/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-[2-(1-methylimidazol-2-yl)ethyl]vinyl]quinoline-3-carboxylate (0.36 g, 15%) as an oil.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:26](O)(=O)[CH3:27]>CO.O>[CH2:1]([N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:26][CH3:27]
Reactant: CC(=O)O
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCN1CC(O)C(O)C(O)C1(CO)CNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2.96 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Example 3) are dissolved in a mixture of 40 ml of methanol, 2 ml of water and 2.7 ml of acetic acid, and 5.7 ml of nonylaldehyde are added. The solution is cooled to 5° C. in an ice-bath; 1.35 g of sodium cyanoborohydride are then added. The mixture is stirred for 30 minutes, whilst cooling, and then at room temperature for 24 hours. It is concentrated, the residue is dissolved in 30 ml of methanol/water 6:1 and the solution is discharged onto a column 30 cm long and 3 cm wide which is filled with Amberlite IR 120, H+ form. The column is washed thoroughly with methanol/water in the ratio 8:1 and then eluted with 0.2% strength ammonia in methanol/water 6:1. The pure fractions, determined by thin layer chromatography, are combined and concentrated. 2.6 g of an almost colourless oil are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]([Cl:22])[S:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]([Cl:22])[S:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1csc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1csc(Cl)n1

Procedure:
61.3 Using general method H, 2-chloro-thiazole-4-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 2-chloro-thiazole-4-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. White solid. MS 476.0 ([M+H]+)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)N(Cc2ccccc2)CCC3)cc1
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-methoxyphenyl isocyanate (407 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:9) to give 8j as solid. Yield: 0.588 g, 72.53%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.[N+](=C[C:14]([O:16]CC)=[O:15])=[N-].Cl[CH2:20]Cl>CCCC(C)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:20][C@H:10]2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(OC)cc1
Reactant: ClCCl
Agent: Cl[Ru]Cl
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Solvent: CCCC(C)C
Solvent: Cc1ccc(C(C)C)cc1
Product: COc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of dichloro(p-cymene)ruthenium (II) dimer (250 mg) and 2,6-bis[(4S)isopropyl-2-oxazolin-2-yl]pyridine (240 mg) in dichloromethane (150 ml) was added 1-methoxy-4-vinylbenzene (25 g). To this solution was added ethyl diazoacetate (5.0 g) in dichloromethane (20 ml) over 6 hours. The solution was maintained at room temperature for 18 hours then diluted with i-hexane (200 ml) and passed through a plug of silica (50 g) washing with i-hexane/dichloromethane (1:1, 250 ml). The filtrate was concentrated and the residue taken into methanol (100 ml). Lithium hydroxide (4.0 g) in water (10 ml) was added and the mixture heated at reflux for 4 hours. The resulting solution was concentrated to give a solid which was washed with 1:1 ether/i-hexane (100 ml). The solid was then triturated with 2N HCl and the white precipitate collected to give the subtitle compound (5.1 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[C:10]([CH3:11])=[C:6]([CH2:4][OH:3])[N:7]([CH3:19])[N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(C)c(-c2ccc(Cl)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(-c2ccc(Cl)cc2)nn(C)c1CO

Procedure:
In analogy to the procedure described for example 1 a], 5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-yl]-methanol as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([CH3:43])([CH3:42])[NH:6][C:7]([C:9]1[N:13]2[N:14]=[C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:7]([NH:6][C:5]([CH3:43])([CH3:42])[C:4]([OH:44])=[O:3])=[O:8])=[N:10][N:11]=4)[N:14]=3)[CH2:27][CH2:26]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(NC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.1 %

Procedure:
830 mg of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycine ethyl ester was dissolved in 10 ml of ethanol; 3.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 17 hours. After the ethanol was distilled off, 1 N hydrochloric acid was added to reach pH 4.5. The precipitated crystal was collected by filtration, washed with water and ethanol, and dried, to yield 610 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OCC)(OCC)[O:15][CH2:16][CH3:17].C(=O)(O)[O-].[CH2:28](O)[CH3:29]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH2:28]([O:13][C:10]([O:15][CH2:16][CH3:17])([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][CH3:12])[CH3:29]
Reactant: CCO
Reactant: CCC(=O)c1ccc(C(C)C)cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Product: CCOC(CC)(OCC)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 75.1 %

Procedure:
48 ml of absolute ethanol and 1 g of p-toluenesulphonic acid are placed in a round flask which is fitted with a stirrer, thermometer, condenser and dropping funnel. Now, there are added dropwise within 30 minutes while stirring 181.5 g of p-isopropyl-propiophenone and subsequently within 1 hour 152.5 g of triethyl orthoformate. The temperature is held at 30° C. by external cooling. The mixture is subsequently stirred for a further 22 hours at 20°-25° C. The mixture is then adjusted to pH 8 with 5 g of triethylamine and thereupon poured into 50 ml of 5% bicarbonate solution and 80 g of ice. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 5% bicarbonate solution and, after the addition of 0.3 g of sodium carbonate, the solvent is removed by evaporation under a vacuum and the residue is distilled over a 15 cm column. There are obtained 193.6 g of p-isopropyl-propiophenone diethyl ketal (yield: 75.1% of theory). B.p.=66° C./0.05 mmHg; nD20 =1,4778; d420 =0,9305.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[ClH:26].CO>>[ClH:26].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 75 (90.7 mg) and 10% hydrogen chloride/methanol solution (2 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (90.4 mg) as light yellow powdery solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]1[CH2:18][CH2:17][C:16]2[S:19][C:20]([NH:25][C:26]([O:28][CH2:29][CH:30]3[C:42]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:36]4[C:31]3=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]1[O:14][CH2:15][C:16]2[S:19][C:20]([NH:25][C:26]([O:28][CH2:29][CH:30]3[C:42]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:36]4[C:31]3=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:21]([C:22]([OH:24])=[O:23])[C:17]=2[CH2:18]1
Reactant: O=C(Nc1sc2c(c1C(=O)O)OC(CN1C(=O)c3ccccc3C1=O)CC2)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1sc2c(c1C(=O)O)CC(CN1C(=O)c3ccccc3C1=O)OC2)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the above Wang-Resin methansulfonyl ester and 5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(9H-fluoren-9-ylmethoxy-carbonylamino)-4,7-dihydro-5H-thieno[2,3]pyran-3-carboxylic acid (4.85 g, 8.4 mmol) was added N-methylpyrrolidinone (45 ml). Cesium carbonate (2.2 g, 6.7 mmol) was added and the reaction stirred under nitrogen for 16 h and then at 80° C. for 36 h. The mixture was cooled to room temperature, the resin filtered off, washed with water, methanol, and dichloromethane repeatedly and dried in vacuo for 2 h affording 5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(9H-fluoren-9-ylmethoxy-carbonylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid Wang-Resin ester.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C)C=O.C(OCC)(=O)C>[Si:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 108 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (178 g) in N,N-dimethylformamide (500 ml) were added imidazole (93.9 g) and t-butyldimethylsilyl chloride (93.9 g), and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (2.0 l) and washed in turn with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-4-t-butyldimethylsilyloxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (260 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:13]([O:12][C:10]([C:9]1[S:15][C:3]([C:4]([OH:6])=[O:5])=[CH:2][N:8]=1)=[O:11])[CH3:14]
Reactant: O=C(O)C(=O)CBr
Reactant: CCOC(=O)C(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ncc(C(=O)O)s1
Yield: 47.8 %

Procedure:
Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2-thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHCO3 and extracted with EtOAc (2×250 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (2×250 mL) The combined extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification.