Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[NH:19][N:18]=2)[CH2:13][CH2:12]1.O.O.Cl[Sn]Cl>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[O:21][C:20](=[O:22])[NH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Yield: 82.6 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17].[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>>[ClH:1].[CH:18]1([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=3[O:13][CH3:14])[C:4]2=[O:17])[CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Reactant: O=C1CCC1
Agent: Cl
Product: COc1ccc2c(c1OC)CCC(NC1CCC1)C2=O

Procedure:
In a manner similar to that of Reference Example 3, 10.5 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is reacted with 10 volume parts of cyclobutanone. The procedure yields 8.2 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride. Melting point: 146°-164° C (decomposition).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH3:25])[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CNCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)CCN(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 37.5 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), N,N,N′-trimethylethylenediamine (0.073 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-[2-(dimethylamino)ethyl]-N2-methyl-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.058 g) as its hydrochloride salt after normal phase HPLC purification and treatment with 4 N hydrochloric acid in dioxane. MS (ESI) m/z 344 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]2[S:29][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=3)[N:30]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(-c2csc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Yield: 100.2 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-bromo-3′-methoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with diethyl ether and little ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(3-methoxy-phenyl)-thiazol-2-yl]-amine as a light green solid. MS ISP (m/e): 393.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.72 (s, 1H), 9.31 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.54-7.51 (m, 4H), 7.35 (t, 1H), 7.28 (d, 1H), 6.90 (d, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[C:20]1([C:25]([NH:27][NH2:28])=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:28][NH:27][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: NNC(=O)c1cccs1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (47 mg) in ethanol (1 ml) was added thenohydrazide (27 mg) and the mixture was stirred at room temperature for 1 hour, and then added sodium cyanoborohydride (20 mg) and acetic acid (0.25 ml) and the mixture was stirred for 1 hour. Aqueous sodium bicarbonate was added and extracted with chloroform and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S) -5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane as a residue and the residue was dissolved in methanol (2 ml) and added 1N aqueous sodium hydroxide (0.4 ml) and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with chloroform. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane (55 mg).
Reaction SMILES: C(O[CH:4](O)[CH2:5][C:6]1[C:18]([CH3:19])=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:20])[CH:7]=1)C.[NH2:22][C@@H:23]([CH3:33])[C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[OH:25]>[C].[Pd].O1CCCC1>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[C@@H:23]([NH:22][CH2:4][CH2:5][C:6]1[C:18]([CH3:19])=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH3:20])[CH:7]=1)[CH3:33]
Reactant: CCOC(=O)COc1cc(C)c(CC(O)OCC)cc1C
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(C)c(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A suspension of ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate (5.4 g), 10% palladium carbon (50% wet, 1.4 g), (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (3.0 g) and tetrahydrofuran (30 g) was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and washed with water, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate (7.3 g).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13](N)=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].[I:20]CI>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([I:20])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: ICI
Agent: CC(C)CCON=O
Product: O=[N+]([O-])c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
Add isoamyl nitrite (18.6 g, 160 mmol) to a suspension of 4-fluoro-3-nitrophenylamine (5.0 g, 32 mmol) in diiodomethane (150 mL). Stir under nitrogen at room temperature for 1 h. Heat at 70° C. for 1 h. Cool to room temperature and concentrate. Dilute with dichloromethane (500 mL) and water (100 mL). Collect the organic, concentrate and purify (silica gel chromatography, eluting with a gradient of 100:0 to 80:20 hexanes:ethyl acetate), to give the title compound as a yellow oil (1.22 g, 14%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[C:40]([CH:38]1[CH2:39][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1)#[N:41]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: N#CC1CNC1
Agent: Cl
Product: CC(C(=O)N1CC(C#N)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and azetidine-3-carbonitrile hydrochloride (Asta Tech, Inc. and Cat. No. 52028). LCMS (M+H)+: m/z=538.2.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[C:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:7][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([C:21](=[O:40])/[N:22]=[C:23]4\[S:24][C:25]5[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=5[N:27]\4[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:9][CH:10]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:7][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([C:21](=[O:40])/[N:22]=[C:23]4\[S:24][C:25]5[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=5[N:27]\4[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCCO
Yield: 82.3 %

Procedure:
Compound 94E (0.91 g, 1.351 mmol) in THF (30 mL) and methanol (5 mL) was treated with NaBH4 (0.102 g, 2.7 mmol). The reaction mixture was heated under reflux for 1 hour. The solvents were removed under vacuum. The residue was re-dissolved in EtOAc and treated with water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give 0.75 g of the title compound 94F (82%): APCI (+)LC/MS: 675 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:44])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: NCC(O)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 3-amino-propane-1,2-diol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C38H49Cl2N6O5 [(M+H)+] 739.3136, observed 739.3139.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:11]I>>[CH:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:2]
Reactant: CCc1ccncc1C#N
Reactant: CI
Product: CC(C)c1ccncc1C#N

Procedure:
By the reaction in the same manner as in Example 64-i) using 4-ethylnicotinonitrile (2.95 g) and methyl iodide (7 ml), the title compound (1.90 g) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][CH3:28])[C:38]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9](/[CH:11]=[N:12]/[CH3:13])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: C/N=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine (0.9 g) in methanol (25 ml) and tetrahydrofuran (10 ml) under nitrogen was added sodium borohydride (0.17 g) and molecular sieves. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo, quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo to give a crude product which was purified using flash chromatography to give (2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (342 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2S(C2C=CC=CC=2)(=O)=O)=[CH:5][CH:4]=1.[Li]CCCC.[CH:26](=[O:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[CH3:28][CH:27]([CH3:29])[C:26]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([S:2][CH3:1])[CH:11]=2)=[O:30]
Reactant: CSc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc(C(=O)C(C)C)[nH]c2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-(methylthio)-1-(phenylsulfonyl)-1H-indole (890 mg, 2.93 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen was added n-BuLi (5.86 mL, 14.65 mmol, 2.5 M). After stirring for 30 min, isobutyraldehyde (1.05 g, 14.65 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and quenched with sat. aq NH4Cl (10 mL) at 0° C. and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluted with (petroleum ether/EtOAc 20:1) to give 2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one (440 mg, 64.28% yield) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1>C(O)C.[Ni]>[Br:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Br)cc(N)c1N

Procedure:
A solution of 15 g (64.9 mmol) of 4-bromo-2-methyl-6-nitro-aniline in 300 ml of ethanol is hydrogenated in the presence of 1.5 g of Raney nickel for 4 hours at approximately 27° C. The reaction mixture is then filtered and concentrated by evaporation. The title compound is obtained in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13].Cl.[CH3:20][N:21]([CH3:26])[CH2:22][C:23]([Cl:25])=[O:24]>ClCCl>[ClH:25].[CH3:18][O:17][C:15]([NH:14][C:12](=[S:13])[NH:11][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]#[N:10])=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])=[O:16]
Reactant: COC(=O)NC(=S)Nc1ccc(SC#N)cc1N
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1NC(=O)CN(C)C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A stirred suspension of 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene (5.6 g.) in dichloromethane (190 ml.) was treated in one portion at room temperature with N,N-dimethylglycyl chloride hydrochloride (3.82 g.). The stirring was continued for one hour and the mixture was allowed to stand overnight. The solid was filtered off and recrystallised from methanol to give 1-(3-methoxycarbonyl-2-thioureido)-2-(2-dimethylaminoacetamido)-4-thiocyanatobenzene hydrochloride (4.35 g.), m.p. 192°-193° C. (with decomposition).
Reaction SMILES: C[O:2][C:3](OC)([CH3:26])[CH2:4][C:5]1[C:10]([F:11])=[C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24].Cl>C1COCC1.CO>[C:3]([CH2:4][C:5]1[C:10]([F:11])=[C:9]([N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=[O:2])[CH3:26]
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
2-(2,2-Dimethoxypropyl)-3-fluoro-4-phthalimidonitrobenzene (5.5 g, 14 mmol) was suspended in a mixture of THF (200 ml) and methanol (100 ml). HCl 2N (1 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. The solvents were evaporated off and the residue redissolved in methylene chloride, dried (MgSO4), filtered and the solvent evaporated off. The residue was triturated in pentane and collected by filtration to give 2-(acetylmethyl)-3-fluoro-4-phthalimidonitrobenzene (4.8 g, 100%) as a pale yellow solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:17]=3)[C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:16]1[N:17]=[C:13]([C:11]2[C:10]([C:25]([F:27])([F:28])[F:26])=[N:9][NH:8][CH:12]=2)[S:14][CH:15]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)cs3)c(C(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1n[nH]cc1-c1nc(Nc2ccccn2)cs1
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 43636.4 %

Procedure:
According to Scheme 3 Step 2: A solution of 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine (0.22 mmol, 94 mg) in TFA (1 mL) was stirred under microwave heating at 140° C. during 5 minutes then at 150° C. during 5 minutes. The solution was dropwise poured onto a saturated aqueous solution of Na2CO3 and filtered. The crude compound was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 93:6.3:0.7) as eluent to yield N-(pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine (96 mmol, 30 mg, 44%) as a slightly orange solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>C(#N)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Reactant: CC(C)(O)CN
Solvent: CC#N
Product: CC(C)(O)CNCC(=O)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 100 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and 1-amino-2-methyl-propan-2-ol (237 mg, 2.66 mmol) in acetonitrile (3 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (57 mg, 100%, HPLC 0.473 min 100%), MS (ISP) m/e=429.3 [(M+H)+].