Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[C:38]([O:41][CH2:42][C:43](Cl)=[O:44])(=[O:40])[CH3:39]>O1CCCC1>[C:38]([O:41][CH2:42][C:43](=[O:44])[NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:12]=3)=[N:6][N:5]2[CH:30]=1)(=[O:40])[CH3:39]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 80.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.725 mmol), triethylamine (152 μL, 1.08 mmol), 2-chloro-2-oxoethyl acetate (94 μL, 0.870 mmol) and tetrahydrofuran (7 mL) as starting materials and in the same manner as in Example 388, the title compound (299 mg, 80%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2O>[Pt].C(O)C.[OH-].[NH4+]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2ncc(N)cc2c1
Yield: 64.5 %

Procedure:
Catalyst (0.10 g of 10% platinum on carbon) was added to a solution of 6-methyl-3-nitroquinolin-4-ol (1 g) in ethanol (25 mL) and ammonium hydroxide (0.5 mL). The mixture was reduced on a Parr apparatus at ambient temperature under a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and then concentrated under vacuum. The residue was combined with water and heated. Hydrochloric acid was added dropwise until all of the solid had dissolved. Activated carbon was added to the solution. The mixture was filtered. Hydrochloric acid (2 mL of 12N) was added to the filtrate. This recrystallization was run three times to provide 0.50 g of 3-amino-6-methylquinolin-+4ol hydrochloride, m.p. >310° C. Analysis: Calculated for C10H10N2O.HCl: % C, 57.02; % H, 5.26; % N, 13.30; Found: % C, 56.92; % H, 5.16; % N, 13.24.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([CH3:24])[N:3]=1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CN(C)C(=O)C>[NH2:31][C:30]1[N:32]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][C:4]([CH3:24])=[C:5]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:22])([F:21])[F:23])[CH:11]=3)[N:6]=2)[N:29]=1
Reactant: N=C(N)N
Reactant: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(N)nc(N)c2nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 4, using 1.1 grams (0.003 mole) of 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]-6-methylpyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide, yielding 2,4-diamino-6-[3,5-di(trifluoromethyl)phenyl]-7-methylpteridine.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16](=O)[CH2:17]Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:23][C:21]1[S:22][CH:17]=[C:16]([C:10](=[N:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccccc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccccc1)c1csc(N)n1
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
A solution of ethyl 2-benzyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.4 g.), thiourea (17.5 g.) and sodium acetate (31.3 g.) in a mixture of water (130 ml.) and ethanol (130 ml.) was stirred at 40° to 45° C. for 2.5 hours. The resultant solution was adjusted to pH 6.5 with aqueous sodium bicarbonate and the precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetate (syn isomer, 39.78 g.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:20](O)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](O)=[O:18])=[CH:9][CH:8]=1>C1COCC1>[C:10]1([CH2:17][OH:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:20][OH:21])=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(CO)c2ccccc12
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A dry 3-neck, 1 L flask equipped with a N2 inlet and dropping funnel is charged with dry THF (200 mL) and LiAlH4 (1.90 g, 0.050 mole). To the stiffed mixture is added via the dropping funnel a hot solution of naphthalene-1,4-dicarboxylic acid (4.32 g, 0.020 mole) in THF (200 mL) over a period of about 1 hour. The resulting mixture is stirred without heating for 90 minutes and then is heated to reflux temperature. After 2 hours, additional LiAlH4 (40 mL of a 1.15 M solution in THF) is added and refluxing continued for 90 minutes. The reaction is stirred at room temperature overnight, then is quenched carefully with THF-water (3:1), acidified to PH <4 with 2N hydrogen chloride, transferred to a separatory funnel and extracted (3 times) with ether. The combined ether extracts are washed with water (2 times), dried (sodium sulfate), filtered, and concentrated to give a white solid (3.68 g). The solid is crystallized from ethyl acetate-hexane, giving (2.68 g) as white crystals, mp 124°-126° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:37]([C:35]3[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[O:38])=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 88.3 %

Procedure:
The procedure of Example 4, step (c) was followed using 145 mg (0.358 mmol) of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (as prepared in the previous step), 70 mg of 10% palladium on carbon (50% by weight water), 49.1 mg (358 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 62.4 μL (0.716 mmol) of oxalyl chloride, and 93.6 μL (0.537 mmol) of DIEA. Chromatography on a 20-g silica SPE column with 20-40% EtOAc-dichloromethane followed by recrystallization from EtOAc-hexane afforded 156 mg (88%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H, J=8.9, 2.6 Hz), 3.58-3.60 (m, 4H), 3.10 (br s, 4H), 2.97-3.00 (m, 2H), 2.70-2.75 (m, 2H), 1.82-1.85 (m, 2H), 1.55-1.65 (m, 1H), 1.49 (s, 9H), 1.45-1.55 (m, 2H, partially obscured by t-Bu peak) and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O4, 494.3 (M+H), found 494.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([O:15]C)=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18]>[OH-].[Na+].CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:17]([F:20])([F:18])[F:19]
Reactant: COC(=O)c1cn(C)c2cc(OC)c(C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1C(F)(F)F)c(C(=O)O)cn2C
Yield: 88 %

Procedure:
The trifluoromethylindole ester (D25, 0.67 g, 2.33 mmol) was heated under reflux in a mixture of 10% aqueous sodium hydroxide (5 ml) and methanol (10 ml) for 30 min. The mixture was then diluted with water to dissolve all solid and extracted with dichloromethane. The aqueous phase was acidified with 5M hydrochloric acid and the precipitate was filtered off and dried to give the title compound (0.56 g, 88%), mp. >247° C. (decomp.)
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:45][O:46][C:47](=[O:64])[C@@H:48]([NH2:63])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][C:57]2[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:64])[C@@H:48]([NH:63][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][C:57]2[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=2)=[CH:54][CH:55]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccncc2)cc1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccncc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Yield: 40.1 %

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (57 mg) was prepared from (S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-Amino-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride (63 mg) following general procedure A. LC-MS (m/z) 858.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[O:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[O:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3[nH]2)o1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of the compound obtained in Example 11 (3) (20 mg) in N,N-dimethylformamide (2 ml), 60% sodium hydride (4.4 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes, followed by addition of 4-fluorobenzyl bromide (26 mg), and the reaction mixture was stirred for further 30 minutes. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with toluene. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 18 mg of the desired product as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:29])=[C:5]([N+:30]([O-])=O)[CH:4]=1)#[N:2]>CO.[Pd]>[NH2:30][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[C@@H:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:11](=[O:28])[N:10]1[CH3:29]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 5.5 h

Procedure:
Under argon, (4R)-4-(4-cyano-2-nitrophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (6.0 g, 11.3 mmol) was dissolved in methanol (420 ml). 10% palladium on activated carbon (5.5 g) was then added, and the mixture was hydrogenated at RT and atmospheric pressure for 5.5 h (strictly monitored by HPLC). The reaction mixture was then filtered off over kieselguhr, and the filter residue was washed with methanol (1000 ml). The filtrate was concentrated and the crude product was subjected to flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 2:1). The title compound was obtained as a solid (2.28 g, 40% of theory).
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[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14](O)=[O:15].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[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[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:13][C:14]([Cl:24])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid (270 mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.16 mL, 1.88 mmol), followed by N,N-dimethylformamide (1 drop). After the gas ceased to produce, the reaction mixture was stirred at room temperature for 2 hours. After the mixture was concentrated in vacuo, the residue was diluted with dichloromethane and concentrated in vacuo again to afford 280 mg of the product (yield was 90%), which was used for next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45](O)=[O:46])=[C:43]([CH3:51])[N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45]([NH:1][CH2:2][CH2:3][CH:4]([N:6]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]3[N:15]=[CH:16][S:17][CH:18]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:46])=[C:43]([CH3:51])[N:42]=1
Reactant: CC(CCN)N1CCC(NCc2cscn2)CC1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(NCc2cscn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
Following general procedure E: to a stirred solution of [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiazol-4-ylmethyl-amine (0.320 g. 1.19 mmol), EDCI (0.252 g, 1.31 mmol) and HOBt (0.177 g, 1.31 mmol) in DMF (5 ml) was added 6-chloro-2,4-dimethyl-nicotinic acid (0.243 g, 1.31 mmol) followed by DIPEA (343 μL, 1.78 mmol) and the resulting mixture was stirred at 25° C. for 16 hours. Standard workup and purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2) afforded 6-chloro-2,4-dimethyl-N-(3-{4-[(thiazol-4-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (0.42 g, 81%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.CC(O)C>ClCCl>[CH2:1]([S:8]([C:9]1[N:10]=[CH:11][C:12]([Br:15])=[CH:13][N:14]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc(SCc2ccccc2)nc1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=S(Cc1ccccc1)c1ncc(Br)cn1
Yield: 91 %

Procedure:
The oxidation of 2-benzylthio-5-bromopyrimidine was carried out using one molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, initially at -10° C. and then at 0° C., as described in Example 40 above; yield 91%, m.p. 101° C. (iPrOH). 1H NMR (CDCl3); δ4.26 and 4.31 (CH2), 7.16 (Ph), 8.80 (H-4, H-6).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([S:14][CH2:15][CH3:16])[N:3]=1.[CH3:17][NH2:18]>CO>[CH2:15]([S:14][C:4]1[N:3]=[C:2]([CH2:17][NH2:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)[CH3:16]
Reactant: CN
Reactant: CCSc1nc(Cl)cc(-c2ccccc2)n1
Solvent: CO
Product: CCSc1nc(CN)cc(-c2ccccc2)n1
Temperature: 30 °C

Procedure:
A mixture of compound 4-chloro-2-ethylsulfanyl-6-phenyl-pyrimidine (1 g, 4 mmol) and aqueous methylamine (0.74 g, 24 mmol) in methanol (20 mL) was stirred at refluxing temperature for 16 hours under nitrogen atmosphere. The reaction mixture was then cooled to temperature in the range of 20-40° C. The solid separated was filtered off and dried under reduced pressure. It was finally titrated with petroleum-ether to afford the title compound as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:28][O:27][C:25](=[O:26])[CH2:24][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 4-{[(tert-butoxycarbonyl)amino]methyl}-4′-hydroxy-1,1′-biphenyl (2.05 g, 6.85 mmol), prepared in the previous step, methyl bromoacetate (648 μL, 6.85 mmol) and potassium carbonate (4.73 g, 34.2 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 20 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(4′-{[(tert-butoxycarbonyl)amino]methyl}[1,1′-biphenyl]-4-yl)oxy]acetate (2.46 g, 97%) as an off-white solid, mp 111-113° C. Elemental Analysis for C21H25NO5. Calc'd: C, 67.91; H, 6.78; N, 3.77 Found: C, 67.70; H, 6.74; N, 3.72
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: N#Cc1cccc(Sc2ccccc2)c1
Yield: 85.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzonitrile (229 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-cyanophenyl phenyl sulfide (181 mg, 86% yield) as colorless liquid. Column chromatography solvent (hexane/ethyl acetate=25/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.30-7.45 (m, 9 H). 13C NMR (CDCl3, 75 MHz) δ 140.2, 133.6, 132.9, 132.3, 131.7, 130.0, 129.7, 129.6, 129.1, 118.5, 113.5. MS (EI) m/z (relative intensity) 211 (30), 185 (20), 134 (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:34])C(=O)C1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]2[C:23]([I:34])=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Product: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 550 mg (1.5 mmol) [3-(2-amino-6-methyl-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (GP40) and 336 mg (1.5 mmol) NIS. Yield: 733 mg (99%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([C:22]2([OH:25])[CH2:21][CH2:20][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: CCCCCC1CCC(=O)CC1
Reactant: CCOc1ccc(Br)c(F)c1Cl
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Temperature: 43 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
2.9 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 30.0 g of 1-bromo-3-chloro-4-ethoxy-2-fluoro benzene (1) dissolved in 80 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 46° C., followed by stirring for 90 minutes. Thereafter, 19.0 g of 4-pentylcyclo hexanone dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 44° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 39.5 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-pentylcyclohexanol (3). The resulting compound (3) was a yellow oily matter.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O.[NH3+:14]N>O.[Ni]>[NH2:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[NH3+]
Agent: [Ni]
Solvent: O
Product: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 14 h

Procedure:
Glucose (0.55 mol; 100 g) was dissolved in 500 ml of H2O, and 40 ml of an 80% hydrazinium hydrate solution (1 mol) were added. The mixture was stirred slowly for 14 h and filled into a high pressure autoclave. Freshly activated Raney nickel (20 g) was added and the mixture was hydrogenated for 3 h at 50° C. while stirring with about 1000 r.p.m. The autoclave was depressurized and the product-catalyst mixture was filtered. The blue filtrate was treated with diacetyldioxime (2,3-butanedionedioxime) to remove the dissolved nickel. The product was concentrated to a clear yellowish syrup and was crystallized in the refrigerator. The white crystals were filtered off and washed with MeOH. If necessary the product was purified using the oxalate method of J. W. Long, G. N. Bollenbach in "Methods of Carbohydrate Chemistry" ed. by R. L. Whistler and M. L. Wolfrom, Academic Press N.Y. 1963, Vol. 2, P. 79). Yield: 80 g ( 80%), m.p.: 127° C.