Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
In methanol (284 ml)is suspended 2',3',4'-trichloroacetophenone (94.7 g), and thereto is added sodium borohydride (7.6 g) at 15° C.-25° C. The mixture is stirred at 25° C. for two hours, and evaporated to remove the methanol. To the residue is added 2N hydrochloric acid (110 ml), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated to remove the solvent to give crude 1-(2,3,4-trichlorophenyl)ethanol (95 g).
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH:24]([CH3:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[O:22])[CH:10]=1)C1C=CC=CC=1.[BrH:30]>C(O)(=O)C>[BrH:30].[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[CH:9]=[CH:10][C:11]([C:21]([O:23][CH:24]([CH3:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[O:22])=[N:12]2
Reactant: CC(CN(C)C)OC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Br
Solvent: CC(=O)O
Product: CC(CN(C)C)OC(=O)c1ccc2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 2-dimethylamino-1-methylethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.4 g) with hydrogen bromide in acetic acid (15 ml, 48%) as described in Example 33d gave 2-dimethylamino-1-methylethyl 5,7-dichloroquinoline-2-carboxylate hydrobromide (0.32 g), m.p. 228° C. (dec). δ (360 MHz, DMSO-d6) 1.37 (3H, d, CHCH3), 2.86 (6H, s, N(CH3)2), 3.59 (2H, m, CH2N), 5.47 (1H, m, CO2CH), 6.81 (1H, s, 3-H), 7.45 (1H, d, 6-H), 8.05 (1H, d, 8-H), 9.45 (1H, bs, NH) and 12.02 (1H, bs, NH). (Found: C, 39.67; H, 3.93; N, 5.94%. C15H16Cl2N2O3. 1.4HBr requires C, 39.47; H, 3.84; N, 6.14 %).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:23]C)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: CCCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 68 %

Procedure:
6-Amino-9-benzyl-2-butoxy-8-methoxypurine (20 mg, 0.061 mmol) in concentrated hydrochloric acid (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered, washed with water, and the crude product was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (13 mg, yield 68%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5](O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:19])=O>C(O)C>[NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([Cl:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: Cn1c(O)nc(-c2ccncc2)c(N)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cn1c(Cl)nc(-c2ccncc2)c(N)c1=O
Temperature: 100 °C

Procedure:
5-Amino-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.46 mmol) was suspended in phosphorousoxychloride (230 mmol) at 0° C. and 2 mL ethanol was added. The reaction was heated to 100° C. overnight. The solvent was removed under vacuum. The solid was suspended in methylene chloride and collected by filtration. M+1=237.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36]([CH2:40][NH2:41])=[CH:35][CH:34]=[CH:33]3)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[CH3:43][C:44]1([CH3:52])[CH2:49][NH:48][CH:47](SC)[NH:46][CH2:45]1>C(Cl)Cl>[C:21]1([S:27]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36]([CH2:40][NH2:41])=[CH:35][CH:34]=[CH:33]3)(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:40][NH:41][C:47]3[NH:46][CH2:45][C:44]([CH3:52])([CH3:43])[CH2:49][N:48]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ccc(S(=O)(=O)c3ccccc3)cc21
Reactant: CSC1NCC(C)(C)CN1
Agent: Cl
Agent: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: ClCCl
Product: CC1(C)CN=C(NCc2cccc3ccc(S(=O)(=O)c4ccccc4)cc23)NC1
Temperature: 150 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is prepared from 7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one following the procedures of Examples 1 and 2. C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and 5,5-dimethyl-2-methylsulfanyl-hexahydro-pyrimidine hydrochloride are added to methylene chloride, and the reaction mixture is heated to gentle reflux until all of the solvent is evaporated. The reaction mixture is heated to 150° C. and then cooled. The resulting mixture is basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography to give (7-benzenesulfonyl-naphthalen-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)=[N:7]1.CO.[ClH:45]>C(OCC)C>[ClH:45].[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5ccn(Cc6cc(F)cc(F)c6)n5)c4c3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1cc(F)cc(Cn2ccc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)n2)c1
Yield: 62.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (27 mg, 0.047 mmol) was deprotected in methanol/HCl in diethyl ether (2/1 ml) to afford 15 mg (62.5% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 9.10-9.00 (bs, 2H), 8.598-8.52 (m, 2H), 7.91-7.89 (m, 2H), 7.60-7.57 (d, 2H), 7.17-7.00 (m, 4H), 6.71-6.70 (d, 1H), 5.41 (s, 2H), 3.23 (s, 5H). MS: m/z=471.3 (M+1), HPLC: 97.74% in method B.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].[NH2:16][CH2:17][C@H:18]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:30]([O:29][C:27]([NH:26][C@@H:18]([CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
354 mg (1.7 mmol) of 4-(2-methoxycarbonyl-ethyl)benzoic acid and 500 mg (1.7 mmol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of O-((cyano-(ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine, and the mixture was stirred at room temperature for 7 hours at pH 7-8. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed three times each with KHSO4 solution and NaHCO3 solution until neutral. The organic phase was separated off and dried and the solvent was removed by distillation in vacuo. Yield 770 mg. MS (ES+): m/e=485.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[N:15](COCC[Si](C)(C)C)[CH:14]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[CH:12]=1)[C:5]([N:7]([CH3:8])[CH3:9])=[O:6]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(C(=O)N(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 82 %

Procedure:
(S)-3-Hydroxy-N,N-dimethyl-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzamide (44 mg, 0.06 mmol, 89% purity) was treated with trifluoroacetic acid (880 μl, 11.42 mmol) and a solution of ammonia (7N in methanol, 880 μl, 6.16 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 27 mg (85% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:28]C(=O)C)[CH:20]=[C:21]([N:23]5[CH:27]=[CH:26][CH:25]=[CH:24]5)[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[N:7]=[N:6]1.[OH-].[Na+]>C(O)C>[NH2:28][C:19]1[CH:18]=[C:17]([N:14]2[C:13]3[CH:32]=[CH:33][C:10]([C:8]4[N:7]=[N:6][N:5]([CH2:4][CH2:3][C:2]([CH3:35])([OH:1])[CH3:34])[CH:9]=4)=[CH:11][C:12]=3[N:16]=[CH:15]2)[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH:20]=1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cn(CCC(C)(C)O)nn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)nn1
Temperature: 80 °C
Yield: 58 %

Procedure:
To a solution of the compound of Example 112 (150 mg, 0.32 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (160 mg, 4 mmol, 12.5 eq.) and the mixture was heated at 80° C. for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 58% yield (80 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1c(OCc2ccccc2)cccn1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1c(O)cccn1Cc1ccccc1

Procedure:
1-Benzyl-3-benzyloxy-1H-pyridin-2-one (Ghosh et al, J. Org. Chem. 1989, 54, 5073) is dissolved in anhydrous methanol (10 mL) and to the thoroughly degassed solution is added a catalytic amount of Pd—C (0.1%). The mixture is hydrogenated under a balloon of hydrogen, until all the starting material is consumed. At the completion, the solution is filtered through Celite™. The solvent is removed in vacuo, and the residue is washed with ether, to afford the desired product. 1H NMR (300 MHz, CDCl3) δ 5.15 (s, 2H), 6.14 (t, J=7.2 Hz, 1H); 6.71 (m, 1H), 7.31 (m, 6H), 9.07 (s, 1H). B. General Procedure for the Three Component Coupling Between Pyridones, Formaldehyde and Amines:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:31])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C1CCCCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCCC4=O)cc3)CC2)c(C)c1
Yield: 76.3 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (205 mg) described in Preparation Example 108 and azepan-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (151 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8](S)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:13][C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Sc1nc2cccc(Cl)c2o1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1nc2cccc(Cl)c2o1

Procedure:
A mixture of 7-chloro-2-mercaptobenzoxazole (14.8 g.) and phosphorus pentachloride (29.2 g.) was heated at 160°-170° under reflux for 3 hours. The flask was fitted with a distilling head and the product was distilled in vacuo. The first two fractions were unreacted phosphorus chloride. Afterwards, the product distilled to give 2,7-dichlorobenzoxazole. This compound was reacted with hydrazine using the method described in procedure (a) of Example 1 and then reacted with acrylonitrile using procedure (c) of Example 1 to give 3-[1-(7-chloro-2-benzoxazolyl)hydrazino]propanenitrile, m.p. 114°-115° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])=[O:6].Cl>C1COCC1.CCOC(C)=O>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[CH2:4][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCC(=O)Nc1c(C)cccc1C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, methylamine (600 mmols) in 300 mL THF was cooled to 0° C. A solution of 2-chloro-N-(2′,6′-dimethylphenyl)acetamide (100 mmols) was dissolved in 200 mL THF, and slowly dripped into the cold methylamine solution. The reaction was stirred overnight. The reaction was filtered, and the filtrate evaporated to yield an oily residue. This was dissolved in EtOAc (100 mL) and treated with 1N HCl (200 mL). The aqueous layer was washed with EtOAc, then basified to Ph 10-12 with 6 N NaOH. The product was extracted into EtOAc (2×50 mL), the organic phase was dried, and the solvent was evaporated to yield N-(2,6-dimethyl-phenyl)-2-methylamino-acetamide (compound (23)) as an oil (12.8 gm; 67% yield).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:19])[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([NH:21][C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[CH:10]=[CH:11][C:12]=4[NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[C:7](=[O:19])[C:6]=3[C:5]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1c2c(Cl)ccc(Cl)c2C(=O)c2c(Cl)ccc(Cl)c21
Product: Cc1ccc(Nc2ccc(Nc3ccc(C)cc3)c3c2C(=O)c2c(Nc4ccc(C)cc4)ccc(Nc4ccc(C)cc4)c2C3=O)cc1

Procedure:
A mixture of 1,4,5,8-tetrachloroanthraquinone (34.6 parts) and p-toluidine (214 parts) was allowed to react at 190° C. for 15 hours. Thereafter, the reaction mixture was cooled, and the precipitate was collected on a suction filter, washed four times with methanol (500 parts) and then twice with hot water (500 parts), and dried to obtain 1,4,5,8-tetra(4'-methylphenylamino)anthraquinone (48.7 parts) as a black solid. The product was recrystallized from toluene to obtain a dark green crystal. The melting point and maximum absorption wave lenggh (λmax measured in acetone) were found to be 268° to 275° C. and 760 nm, respectively.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:11]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][N:7]=2)C(=O)C2=CC=CC=C12.O.NN>CCO>[NH2:5][C:6]1[C:11]([CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1CN1CCCCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ncccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Phthalimidyl)-3-(1-piperidinylmethyl)-pyridine (196 mg, 0.609 mmol) was dissolved in EtOH (95%, 2 mL) at 23° C., and treated with hydrazine monohydrate (0.0320 mL, 0.670 mmol) in a dropwise fashion. The resulting mixture was warmed to reflux and stirred for 3 h at reflux. The solution was treated with additional hydrazine monohydrate (0.150 mL, 3.050 mmol), and reflux continued. After 14 h at reflux, the mixture was cooled to RT, and concentrated using a rotary evaporator to a white paste. The resulting white paste was dissolved in CHCl3: IpOH (3:1, 75 mL), and washed with saturated NaHCO3 (3×50 mL), and H2O (1×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound as a white solid. MS m/z: 192 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:17]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].CS(O)(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:17][C:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(F)ccc12)C1CC(O)CN1C(=O)OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)CC1Cc1c[nH]c2cc(F)ccc12
Temperature: 11 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 6 (10.1 g, 26 mmol) in anhydrous THF (200 mL) was added 2M LiBH4 in THF (26.2 mL, 52 mmol) over ca. 7 min [Note: exothermic; temp. increase: 21.5° C. to 28.2° C.]. After 2.5 h, the pale, yellow-colored solution was cooled to ca. 11° C. and methanesulfonic acid (4.66 g, 48 mmol) was added over ca. 4 min [Note: exothermic; temp. increase to 14.2° C.].
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])[CH2:6]1)(=O)C.[ClH:30].C(O)C>>[ClH:30].[NH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22]3)=[CH:12][C:11]=2[F:29])[CH2:6]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC(NC(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: NC1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A mixture of 20.0 g (50 mmol) of 7-[3-(acetylamino)cyclopentyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, ethyl ester was heated in a mixture of 6.0 M hydrochloric acid/ethanol (20 ml/150 ml) at reflux for 8 hours. The solvent was removed in vacuo and the residue slurried in 200 ml of water and filtered. The filtrate was evaporated in vacuo and the residue triturated in ethanol and filtered. The precipitate was washed with ethanol, ether, and dried in vacuo to give 13.6 g of the title compound.
Reaction SMILES: C1(C[O:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)=O)C=CC=CC=1.Cl[CH2:33][C@@H:34]([OH:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].O(C(C)(C)C)[Li]>CN(C=O)C>[CH3:40][C:39]([CH3:42])([O:38][C:37]([NH:36][CH2:35][C@@H:34]1[O:44][C:9](=[O:8])[N:11]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)[CH2:33]1)=[O:43])[CH3:41]
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CCl
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A solution of phenylmethyl 3,4-dihydro-7-[[(phenylmethoxy)carbonyl]amino]-2(1H)-isoquinolinecarboxylate (Step 3, 5.12 g, 12.29 mmol) and tert-butyl (2S)-3-chloro-2-hydroxypropylcarbamate (which can be prepared according to U.S. patent application, serial No. 60/241122, 3.22 g, 15.36 mmol) in dry DMF (5.6 mL) at 0° C. under N2 is treated with LiOtBu (1M in THF, 29.5 mL, 29.5 mmol) dropwise over 5 mins. The cooling bath is removed, and the resulting mixture is stirred at ambient temperature for 18 hrs, quenched with saturated aqueous NH4Cl (25 mL), diluted with H2O (25 mL) and extracted with EtOAc (50 mL). The EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of EtOAc/heptane (25/75-50/50). Those fractions with an Rf=0.20 by TLC (EtOAc/hexane, 50/50) are pooled and concentrated to give 4.69 g (80%) of the title compound as a white solid, mp 135-137° C. [α]25D=−27° (c 1.00, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][CH:15]([S:22][CH2:23][CH2:24][OH:25])[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(F)cc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: OCCS
Product: CC1(c2ccc(F)cc2)OC(CC(SCCO)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-(4-fluorophenyl)-2-methyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2-mercapto-1-ethanol to provide 2-(4-fluorophenyl)-5-[2-[(2-hydroxyethyl)thio]-2-(3-thienyl)ethyl]-2-methylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.53 and 1.56 (singlets, 3H), 4.39 (m, 1H), 5.56 (overlapped singlets, 1H), 7.08-7.35 (m, 5H), 7.43-7.60 (m, 2H); MS (HR-Cl) m/z 379.0832 (M+H calcd. for C19H20FO3S2 379.0837)
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8](/[CH:11]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[N:9][CH:10]=1
Reactant: Cc1cc(C=O)ncc1OCC(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)F
Yield: 11 %

Procedure:
The title compound is prepared in 11% yield (147 mg, colorless oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde (860 mg, 4.27 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (777 mg, 6.41 mmol) in a similar manner to Step-6 of Amine-49.