Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([SH:14])=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1.[Cl-].Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][NH+:22]=1>C(O)C.O>[F:17][C:4]1([F:3])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([S:14][CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][N:22]=4)=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: COc1c[nH+]c(CCl)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)cc1OC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
6.3 ml of 1N sodium hydroxide solution are added dropwise to a solution, warmed to 50° C., of 0.69 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol and 0.67 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 9 ml of ethanol and 4 ml of water in the course of one minute. On cooling the clear reaction mixture to 20° C., a colorless precipitate separates out after a short time. The mixture is stirred at 20° C. for a further 5 hours and the precipitate is filtered off with suction over a suction filter, rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The beige solid is dissolved in 10 ml of methylene chloride, insoluble constituents are filtered off, the filtrate is concentrated and the residue is made to crystallize by addition of diisopropyl ether after cooling. 1.02 g (90% of theory) of the title compound of m.p. 189°-191° C. are obtained.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([CH2:33][NH2:34])[C:29]([CH3:35])=[N:28]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:34][CH2:33][C:30]4[C:29]([CH3:35])=[N:28][N:27]([CH3:26])[C:31]=4[CH3:32])[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(OC3CCC(=O)CC3)ccc2O1
Reactant: Cc1nn(C)c(C)c1CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1C1CCc2cc(OC3CCC(NCc4c(C)nn(C)c4C)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 100 mg 4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanone (0.30 mmol) in 2 ml of methanol and 0.15 ml of acetic acid at room temperature 124 mg (1,3,5-trimethyl-1H-pyrazol-4-yl-methyl)amine (0.89 mmol) and 56 mg of sodium cyanoborohydride (0.89 mmol) were added in one portion and stirring at room temperature was continued for 2 h. Volatile components were removed under reduced pressure and the resulting residue dissolved in dichloromethane. The organic layer was washed with aqueous 2N sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 132 mg of the title compound were isolated.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24]C)=[C:17]([CH:26]([CH3:28])[CH3:27])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:26]([CH3:27])[CH3:28])[C:18]([OH:24])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
At −78° C., to a stirred solution of (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (2.00 g, 4.94 mmol) in CH2Cl2 (16.6 mL) was added 1M boron tribromide/CH2Cl2 (10.4 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for 1.5 h. The reaction was quenched into crushed ice (18 g), diluted with H2O (20 mL) and extracted with ether. The combined ethereal extracts were washed with brine, dried (MgSO4) and concentrated. The crude product was purified on silica gel eluting with 15% acetone/hexane to give 0.97 g (50%) of the title compound as a white solid, mp 138° C.; 1H NMR (DMSO-d6) δ 1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.34 [septet (under H2O peak), 2H], 3.84 (s, 2H), 7.04 (d, 2H), 7.17-7.25 (m, 3H), 7.44 (s, 2H), 9.11 (s, 1H). IR (KBr) 3400, 2950, 1580, 1320, 1200 cm−1. mass spectrum (EI), m/z 390 (M+). Anal. Calcd. for C26H30O3.0.2H2O: C, 79.24; H, 7.77; N, 0.12. Found: C, 79.27; H, 7.85; N, 0.12.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.[C:45]([OH:48])(=[O:47])[CH3:46].[CH2:49](O)C>>[OH:40][CH:28]([CH2:46][C:45](=[O:48])[O-:47])[CH2:29][N+:31]([CH3:49])([CH3:36])[CH3:32].[CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1
Reactant: CCO
Reactant: CC(=O)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
Carnitine was synthesized as in example 2, except that the NADH regeneration system comprised, in addition to alcohol dehydrogenase, aldehyde dehydrogenase (E.C. 1.2.1.5) which oxidizes the aldehyde (formed by action of alcohol dehydrogenase on ethanol) to acetic acid. Two molecules of NADH were formed from one molecule of ethanol (instead of one in the preceeding example) and the reaction balance was strongly displaced in favour of NADH and acetic acid formation. It was thus no longer necessary to eliminate acetaldehyde as in the preceeding example. The conditions were thus those of example 2, except that 125 units of purified aldehyde dehydrogenase (Boehringer ref. 171.832) were added to the reaction medium and nitrogen bubbling was omitted. After 24 hours, 0.764 g of L-carnitine was formed with a yield of 77.5% with respect to dehydrocarnitine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added morpholine (17 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate) yielding the Compound 48 as a solid (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([Br:32])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Yield: 82.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (78 mg, 0.19 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in CH2Cl2 (0.7 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 77 mg of the title compound as a light yellow solid. MS: (+) m/z 493.25, 495.14 (M+1, 79/81Br).
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Br:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N2CCCc3cc(Br)cc1c32
Reaction time: 5 h

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (10 g) and N-bromosuccinimide (10 g) in DMF (60 ml) was stirred at 7020 C. for 5 hours. After cooling, to the mixture was added ethyl acetate (500 ml) and washed with water and saturated aqueous sodium chloride solution successively, and then dried over anhydrous sodium sulfate. Evaporation of ethyl acetate afforded the title compound. The compound was recrystallized from ethanol to give 14 g (98.4%) as dark red needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH2:9][CH2:10][N:11]([CH3:48])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33](O)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:36]=[CH:37][C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:39][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:50][O:51][CH:52]([O:60][CH3:61])[CH2:53][N:54]([CH3:59])[S:55]([NH2:58])(=[O:57])=[O:56].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:58][S:55]([N:54]([CH2:53][CH:52]([O:51][CH3:50])[O:60][CH3:61])[CH3:59])(=[O:57])=[O:56])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:36]=[CH:37][C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)=[CH:39][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:48])[CH2:10][CH2:9][N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CN(CCN(C)[C@H]1COc2cc(OCc3ccccn3)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)C(=O)OC(C)(C)C
Reactant: COC(CN(C)S(N)(=O)=O)OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3)OC
Temperature: 40 °C

Procedure:
(7R)-7-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, see Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (24 mM) and EDC (3 eq) was added. The mixture was warmed to 40° C. After 2 h the mixture was diluted with DCM and extracted twice with H2O, sat. aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The product was obtained as a yellowish sticky solid and used without further purification (91%). (ES+) m/z 849 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)Cl.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.3 g, 1.2 ml (10 mmol) of Dimethyl-1,3-dioxolane-4-methanol, 3.7 g (3.0 mmol, 3.0 eq) of 4-Dimethyl amino pyridine dried for one hour was added and dissolved with 100 mL of CH2Cl2. Thereafter, 2.3 g (12 mmol, 1.2 eq) of p-Toluenesulfonyl chloride was added, then, [the solution] was stirred for the first 30 minutes dipped in cold water at room temperature under argon atmosphere (colorless transparent). After stirring for 18 hours, the disappearance of the raw materials was checked by TLC, liquid separation was carried out with a separating funnel (organic solvent: CDCl3) and the oil layer was dried with anhydrous Na sulfate. An hour later, cotton plug-filtered and concentrated with an evaporator, [the solution] was the target compound was isolated by silica gel column chromatography (CHCl3→CHCl3:MeOH=100 to 10:1) to obtain an oily liquid (2) (pale yellow transparent to colorless transparent). The obtained liquid was dried overnight and an NMR measurement was carried out. (yield: 1.85 g, 8.3 mmol; yield 83%)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[S:23][C:22]([S:24]([NH:27][NH2:28])(=[O:26])=[O:25])=[CH:21][CH:20]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:28][NH:27][S:24]([C:22]1[S:23][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[CH:20][CH:21]=1)(=[O:25])=[O:26]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNS(=O)(=O)c1ccc(-c2ccccn2)s1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(-c2ccccn2)s1
Temperature: 100 °C
Yield: 23 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-(2-pyridinyl)-2-thiophenesulfonohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 23 mg of the title compound (23%) as a yellow solid in 94.8% purity by HPLC (Rt: 3.68, 5.13, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[F:19][C:20]1[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][C:23](B(O)O)=[C:22]([O:32][CH3:33])[CH:21]=1>>[F:19][C:20]1[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C@H:12]2[O:16][C:15](=[O:17])[NH:14][C@@H:13]2[CH3:18])=[C:22]([O:32][CH3:33])[CH:21]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 240 mg of (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 171 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 412.3 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.79, 7.77 (s, 1H), 7.64, 7.62 (dd, J˜2.5 Hz, 8 Hz, 1H), 7.32, 7.31 (d, J˜8 Hz, 1H), 7.00, 6.95 (d, J=8.5 Hz, 1H), 6.70, 6.67 (d, J=12 Hz, 1H), 6.47, 6.43 (s, 1H), 5.08, 5.04 (d, J=5 Hz, 0.1H), 3.68-3.80 (m, 3.5H), 3.53 (m, 0.5H), 3.21 (m, 1H), 1.19-1.30 (m, 6H), 0.95, 0.77 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[C:15]=1[CH3:33])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([CH:8]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=2)[C:15]=1[CH3:33])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(CC(Cc1ccccc1)C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76.2 %

Procedure:
To a room temperature solution of the methyl ester from Step 2 (40 mg, 0.08 mmol) in 3 mL THF and 5 mL MeOH was added 1 mL of 1M LiOH. The resulting solution was stirred 30 h at room temperature, then quenched with aqueous NH4Cl and concentrated in vacuo. The residue was partitioned between 1M HCl and EtOAc, washed with brine, dried over Na2SO4 and evaporated to give 30 mg of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1Cc1ccccc1

Procedure:
5 g of 2-benzyl-4-chlorophenol, 2.6 ml of chloroacetone, 1.38 g of potassium carbonate and 0.34 g of potassium iodide are dissolved in 50 ml of acetone and boiled under reflux for 20 h. After cooling, the precipitate is filtered, concentrated by evaporation, the residue dissolved in ethyl acetate, the solution washed three times with a 1 n sodium hydroxide solution, then with saturated sodium chloride solution, dried with magnesium sulphate and concentrated by evaporation under vacuum. After recrystallisation from diethylether, 1-(2-benzyl-4-chlorophenoxy)-propan-2-one is obtained as a white powder with a melting point of 65-6° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:11][CH3:12])=[N:4][CH:5]=1)[CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CSc1ncc(C(C)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(C(C)OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
3-Chloro-5-(1-hydroxyethyl)-2-methylthiopyridine (21.9 g, 0.108 mol) was dissolved with stirring in anhydrous DMF (250 mL) and 60% sodium hydride (5 g, 0.125 mol) added in portions. The mixture was stirred at room temperature for 30 minutes and benzyl bromide (17.6 g, 0.103 mol) added dropwise. The mixture was then stirred at room temperature for four hours, diluted with water (400 mL) and extracted three times with ethyl acetate (100 mL). The combined organic extracts were washed twice with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness. Purification of the residue by chromatography over silica (0-5% ethyl acetate:hexane) gave the desired product (25.0 g, 79%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (230 mg, 1.73 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (1.00 g, 3.61 mmol) described in Manufacturing Example 12-1-5 under nitrogen atmosphere at room temperature. Triethylamine (965 μL, 6.92 mmol) was added dropwise to the mixture and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (470 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[I:18]CCI.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([I:18])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: ICCI
Reactant: Clc1ccc(-c2nccs2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Clc1ccc(-c2ncc(I)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 2.3 grams (0.012 mole of 2-(4-chlorophenyl)thiazole in 20 ml of diethyl ether was cooled to -78° C. To this solution was added 4.72 ml of a 2.5M solution of n-butyllithium in hexanes. This mixture was stirred for 30 minutes. A solution of 3.3 grams (0.012 mole) of 1,2-diiodoethane in 15 ml of diethyl ether was added, and the resultant mixture was allowed to warm to room temperature and stir for approximately 18 hours. approximately 50 ml of an aqueous, saturated ammonium chloride solution was added, and the resultant mixture was poured into a separatory funnel. The organic phase was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 2.6 grams of 2-(4-chlorophenyl)-5-iodothiazole as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[C:18]2[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=2[S:16][CH:15]=1)=[O:13].[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[C:18]2[N:19]=[C:20]([NH:30][C@@H:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]3[NH2:31])[N:21]=[CH:22][C:17]=2[S:16][CH:15]=1)=[O:13]
Reactant: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)c(OC)c1
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)c(OC)c1

Procedure:
To a solution of 0.047 g (0.134 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid(2,4-dimethoxy-phenyl)-amide in 1.34 mL of dioxane was added 0.0967 mL (0.806 mmole) of (cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Dichloromethane was added and washed with aqueous sodium bicarbonate. The aqueous layer was washed twice with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.052 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (2,4-dimethoxy-phenyl)-amide as a yellow solid. MH+/Z=428