Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[CH:4]=[O:5].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[CH:4]1[O:16][CH2:15][CH2:14][O:5]1
Reactant: OCCO
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C)c1C1OCCO1
Temperature: 25 °C

Procedure:
A solution of 2.8 g of 2,6-dimethyl-3-nitrobenzaldehyde in 150 ml of toluene was treated with 5 ml of ethylene glycol and 20 mg of p-toluenesulphonic acid. The mixture was heated to reflux for 18 hours, with the water being separated using a separator. The mixture was left to cool to room temperature and was washed twice with water. After drying over anhydrous magnesium sulphate the solvent was evaporated and the crystalline residue was crystallized from hexane. 3.0 g of 2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolane, m.p. 69-71° C., were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17].CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2-iodobenzotrifluoride (0.72 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(2-(trifluoromethyl)phenylsulfanyl)-benzene (0.64 g) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Cl.O1CCOC[CH2:19]1>O1CCOCC1>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C1COCCO1
Reactant: Nc1nc2ccc(CC(=O)O)cc2s1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc2nc(N)sc2c1
Temperature: 75 °C
Yield: 80.8 %

Procedure:
A mixture of 2-(2-aminobenzo[d]thiazol-6-yl)acetic acid (95%, 10.0 g, 45.6 mmol), methanol (50 mL), 4 N HCl/1,4-dioxane (12.0 mL, 48.0 mmol) in 1,4-dioxane (30 mL) was heated at 75° C. for 9 hr and then concentrated under vacuum. The residue was suspended into water (50 mL) and basified to pH 9 with 1N NaOH solution. The title compound (8.19 g, 81% yield) was collected as a pale solid by suction filtration and dried under vacuum at 50° C.
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][CH2:1][C:10]2=[O:11])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(Br)ccc1Cl
Reactant: O=C1CCc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C2C(=O)CCc3ccccc32)ccc1Cl
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Charge an oven dried, argon flushed 25-mL two-necked round bottomed flask equipped with a stirring bar with β-tetralone (1.3095 grams, 8.9575 mmoles) and 5 mL dry dimethylformamide. Cool to 0° C. with an ice bath, add sodium hydride (0.4299 grams, 8.9575 mmoles, 50% oil dispersion) and stir for 25 minutes. Filter the solution through a 5 mL syringe equipped with a bed of celite (dried in an oven) via a double-ended needle into an oven dried, argon flushed 25-mL round bottomed flask equipped with a stirring bar and reflux condenser which had been charged with 4-bromo-2-methoxy-1-chlorobenzene (1.5871 grams, 7.166 mmoles), palladium acetate (0.0079 grams 0.0350 mmoles) and tri(ο-tolyl)phosphine (0.0213 grams, 0.070 mmoles). Heat at about 125° C. (oil bath) for 21 hours, cool to RT and add ethyl acetate and 2N HCl. Separate the layers, extract the aqueous layers with two portions of ethyl acetate, wash the combined organic layers with saturated sodium bicarbonate solution followed by saturated salt solution, dry over magnesium sulfate and concentrate using a Buchi rotavapor to produce the named product.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]([O:31][Si](C(C)(C)C)(C)C)[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:39])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>O1CCCC1.ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:39])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorobenzamide in tetrahydrofuran (5 mL) was added 1 N hydrochloric acid (10 mL) and the reaction mixture was stirred for 16 hours at ambient temperature. After diluting the mixture with dichloromethane (50 mL), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.073 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.66 (br s, 1H), 7.80-7.70 (m, 1H), 6.97-6.85 (m, 1H), 5.29-5.16 (m, 1H), 5.01-4.90 (m, 1H), 4.15-3.90 (m, 4H), 3.71-3.51 (m, 2H), 3.38-3.29 (m, 2H), 2.23-1.90 (m, 3H), 1.80-1.53 (m, 12H), 1.35-1.23 (m, 3H); MS (ES−) m/z 465.2 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:25][CH3:26])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:25][CH3:26])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c1c(OCCN)cccc1n2Cc1ccccc1
Temperature: 85 °C
Yield: 85 %

Procedure:
To a mixture of [(9-benzyl-6-methoxy-9H-carbazol-4-yl)oxy]acetonitrile (0.43 g, 1.26 mmol) in dry THF (20 mL) is added borane-methylsulfide complex (0.36 mL, 3.8 mmol). The mixture is heated at 85° C. overnight. Methanol is slowly added to the mixture until gas evolution ceased. The solvents are removed under reduced pressure. Methanol (20 mL) is added then removed under reduced pressure. Methanol (50 mL) and concentrated hydrochloric acid (10 mL) is added to the mixture and heated at 65° C. overnight. The mixture is neutralized with saturated potassium carbonate and partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL). The CH2Cl2 is dried over anhydrous sodium sulfate and concentrated. Column chromatography with silica gel (60 mL) using 4% CH3OH in CH2Cl2 gave 0.371 g (85%) of the title compound; IR (drift) 1581, 1488, 1467, 1452, 1440, 1343, 1323, 1289, 1271, 1211, 1167, 1150, 1031, 742, 727 cm−1. HRMS (FAB) calcd for C22H22N2O2+H1 347.1759, found 347.1761. % Water (KF): 0.17. 1H NMR (CDCl3) δ3.28, 3.92, 4.28, 5.47, 6.65, 6.95, 7.02, 7.09, 7.21, 7.32, 7.87; Anal. Calcd for C22H22N2O2: C, 76.15; H, 6.41; N, 8.07. Found: C, 75.90; H, 6.38; N, 7.99.
Reaction SMILES: CN[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH:8]=[CH:7]1.CN.N1(CCCN2C3C(=CC=C(NC(C4SC=CC=4)=N)C=3)C=C2)CCOCC1.I.[ClH:47].N1(CCCN2C3C(=CC=C(NC(C4SC=CC=4)=N)C=3)C=C2)CCOCC1.Cl.Cl.CNCCCN1C2C(=CC=C(NC(C3SC=CC=3)=N)C=2)C=C1>>[Cl:47][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH:8]=[CH:7]1
Reactant: Cl
Reactant: CNCCCn1ccc2ccc([N+](=O)[O-])cc21
Agent: CN
Agent: CNCCCn1ccc2ccc(NC(=N)c3cccs3)cc21
Agent: I
Product: O=[N+]([O-])c1ccc2ccn(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Procedure described under Example 40. (Yield: 796.6 mg, greater than 100%) Preparation of N-methyl-3-(6-nitro-1H-indol-1-yl)propan-1-amine (158): Reaction performed as described in Example 40, using methylamine as nucleophile. The product was purified using silica gel column chromatography (2.5-5% 2M ammonia in methanol, 97.5-95% dichloromethane). Yield: 91.7 mg of compound 158 as a dark yellow oil (94.1%). 1H-NMR (CDCl3) δ 8.40-8.39 (d, J=1.8 Hz, 1H), 8.02-7.99 (dd, J=2.1, 9 Hz, 1H), 7.66-7.63 (d, J=8.7 Hz, 1H), 7.42-7.41 (d, J=3 Hz, 1H), 6.60-6.59 (d, J=3.3 Hz, 1H), 4.36-4.31 (t, J=6.9 Hz, 2H), 2.59-2.54 (t, J=6.6 Hz, 2H), 2.43 (s, 3H), 2.07-1.98 (quintet, J=6.7 Hz, 2H) Preparation of N-(1-(3-(methylamino)propyl)-1H-indol-6-yl)thiophene-2-carboximidamide dihydrochloride (159): Reaction performed as described in Example 40, compound 150. Following isolation of the HI salt by precipitation (121.9 mg), the salt was dissolved in ethanol. Treated amberlite resin (3.00 g) was added to the solution, and the mixture stirred at room temperature for 35 minutes. The reaction was diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated to afford a yellow oil. The material was absorbed onto silica gel and purified by silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane). Reaction converted to hydrochloride salt using procedure described in Example 40 for compound 151. Yield: 87.2 mg of compound 159 as a yellow-orange solid. 1H-NMR (DMSO-d6) δ 7.74-7.73 (d, J=3.6 Hz, 1H), 7.61-7.59 (d, J=4.5, 1H), 7.46-7.43 (d, J=8.1 Hz, 1H), 7.21-7.20 (d, J=3 Hz, 1H), 7.11-7.09 (t, J=4.8 Hz, 1H), 6.92 (s, 1H0), 6.60-6.57 (dd, J=1.2, 8.4 Hz, 1H), 6.34-6.33 (d, J=3 Hz, 2H), 4.17-4.12 (t, J=6.9 Hz, 2H), 2.46-2.41 (t, J=6.6 Hz, 2H), 2.25 (s, 3H), 1.87-1.83 (quintet, J=6.7 Hz, 2H). ESI-MS m/z (%): 327 (+, 100).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH:7]=[CH:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][O:4][C:3]1=[O:14]>CO.[Pd]>[CH3:1][N:2]1[C@H:6]([CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CN1C(=O)OC[C@H]1C=Cc1cccs1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)OC[C@H]1CCc1cccs1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.8 %

Procedure:
(4R)-Methyl-4-[2-(thiophen-2-yl)ethenyl]oxazolidin-2-one (18.0 g, 86.0 mmol) obtained in Example 66(d) was dissolved in methanol (150 ml), and 10% palladium-charcoal (4.5 g) was added thereto followed by stirring for 10 hours at room temperature under a hydrogen atmosphere. The palladium-charcoal in the reaction solution was removed by filtration using Kiriyama funnel covered with a silica gel thin layer, and the filtrate was evaporated in vacua. The obtained solid was washed with diethyl ether, and dried to give the title compound (16.5 g, 91% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:25]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O>[CH3:25][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cccc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CCC(c2ccc(-c3cn4cccc4c(=O)[nH]3)cc2)CC1
Reaction time: 0.08 h

Procedure:
3-(4-Piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (50.0 mg; 0.17 mmol) is dissolved in acetonitrile (1.5 mL), 35% aqueous formaldehyde solution (67.0 μl; 0.84 mmol) is added and the reaction mixture is stirred for 5 min. Sodium cyanoborohydride (21.2 mg; 0.34 mmol) is added in small portions and the reaction stirred for 2 h. The reaction mixture is diluted with water, treated with saturated NaHCO3 solution and extracted with ethylacetate (three times). The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product is purified by preparative HPLC. The combined fractions are concentrated in vacuo, the aqueous residue is made basic with saturated NaHCO3 solution, treated with NaCl (solid) and extracted with ethylacetate (four times). The combined organic layers are washed with brine, dried over Na2SO4, filtered off by suction and evaporated to dryness to afford 3-[4-(1-methyl-piperidin-4-yl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as beige solid; HPLC/MS 1.28 min (A), [M+H] 308;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:27](O)(=O)[CH2:28][CH2:29][CH3:30]>O=P(Cl)(Cl)Cl>[CH2:28]([C:27]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:13][CH2:14]3)=[CH:3][C:2]=2[N:1]=1)[CH2:29][CH3:30]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1N
Reactant: CCCC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2cc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2[nH]1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of [4-(3,4-diaminophenyl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone (0.500 g, 1.370 mmol) and butyric acid (0.180 g, 2.040 mmol) was heated to reflux in POCl3 for 12 h. The mixture was cooled to room temperature and then concentrated. The black syrup was poured over 10% Na2CO3 solution, then extracted with ethyl acetate, washed with water and brine. The solvent was removed in vacuo and the residue was purified by column chromatography to yield the title compound as a yellow syrup in 52% yield (0.115 g). 1H NMR (300 MHz, CDCl3) δ 8.90 (br., s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.62-7.42 (m, 2H), 7.36 (d, J=9.2 Hz, 2H), 6.98 (s, 1H), 6.87 (dd, J=2.0, 8.7 Hz, 1H), 4.01-3.91 (m, 2H), 3.33 (t, J=4.8 Hz, 2H), 3.15 (t, J=4.8 Hz, 2H), 3.05-2.95 (m, 2H), 2.79 (t, J=7.4 Hz, 2H), 1.85-1.70 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 155.4, 147.2, 134.5, 134.5, 132.3, 129.3, 127.2, 127.0, 126.8, 126.8, 126.7, 126.7, 126.6, 126.2, 125.4, 121.8, 114.7, 102.5, 102.4, 102.3, 51.4, 51.2, 47.3, 41.9, 31.1, 21.6, 13.8. MS (ES+) m/z 417.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C:13]2[CH:14]=[C:15]([CH:42]=[CH:43][CH:44]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][C@@H:30]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:46].Cl.C(C1ON=C(NC(NC2C=CC=C(OC3C4C(=CC(O[C@H]5CCNC5)=C(OC)C=4)N=CN=3)C=2)=O)C=1)(C)(C)C>>[ClH:46].[ClH:46].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C:13]2[CH:44]=[CH:43][CH:42]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][C@@H:30]5[CH2:34][CH2:33][NH:32][CH2:31]5)=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Agent: Cl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@@H]1CCNC1
Yield: 40 %

Procedure:
Prepared from (R)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate from the previous step (109 mg, 0.176 mmol) according to the procedure described for (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride in Example 96B to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride as a colorless solid (42 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 9.30 (brs, 1H), 8.61 (brs, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7.20-7.40 (m, 4H), 6.99 (m, 1H), 6.02 (s, 1H), 5.05 (m, 1H), 4.01 (s, 3H), 3.10-3.40 (m, 2H), 3.00 (m, 1H), 2.00-2.40 (m, 4H), 1.40 (s, 9H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11]OS(C)(=O)=O)[C:4]=2[CH2:3][CH2:2]1.[C-:17]#[N:18].[Na+]>CS(C)=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][C:17]#[N:18])[C:4]=2[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCc1cccc2c1CCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCc1cccc2c1CCO2
Yield: 99.8 %

Procedure:
A solution of methanesulfonic acid 2-(2,3-dihydrobenzofuran-4-yl)-ethyl ester (1.71 g) in dimethylsulfoxide (14 ml) was treated with sodium cyanide (381 mg) and heated at 80° for 1 h. The suspension was cooled to 20°, diluted with water (14 ml) and extracted with ethyl acetate (2×17 ml). The combined extracts were washed with 5% aqueous sodium chloride (17 ml), dried (Na2SO4) and the solvent evaporated to give the title compound (1.22 g) as a brown oil which crystallised on standing.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][O:9][CH:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:7][C:6]([F:21])([F:20])[CH2:5]1)=[N+]=[N-].[Cl-].[NH4+].[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CCCP(=O)=O>CCO.[Fe].O>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[CH:8]1[CH2:7][C:6]([F:21])([F:20])[CH2:5][CH:4]([NH2:1])[CH2:10][O:9]1)=[O:39]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(F)(F)CC(N=[N+]=[N-])CO1
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Fe]
Agent: CCCP(=O)=O
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC(F)(F)CC(N)CO1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (264 mg, 0.87 mmol) in EtOH (8.8 mL) was added ammonium chloride (360 mg 6.73 mmol) water (0.88 mL) and iron powder (51 mg, 0.91 mmol). The reaction mixture was heated at 80° C. for 16 hr and then cooled to room temperature. The crude slurry was filtered through Celite® washing with DCM (200 mL). The solution was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in isopropanol (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (255 mg, 0.92 mmol) and DIPEA (0.59 mL, 3.50 mmol) were added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.46 mL, 0.96 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) followed by preparative HPLC gave 122 (Diastereomer 2) as a colourless solid (24 mg, 6% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.43 and 9.39 (2s, 1H), 8.09 and 8.07 (2s, 1H), 7.32 (tt, J=8.4, 6.1 Hz, 1H), 7.06-6.96 (m, 2H), 6.19 (s, 2H), 4.92 and 4.81 (d, J=11.4 Hz, 1H), 4.27 and 4.08 (2dd, J=12.5, 5.2 Hz, 1H), 3.88 (dd, J=12.5, 6.4 Hz, 1H), 3.83 and 3.81 (2s, 3H), 3.46-3.36 (m, 1H), 2.65-2.46 (m, 1H), 2.45-2.27 (m, 2H), 1.25 (s, 3H). LCMS (ES+) m/z 485 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([O:22]C(C)(C)C)=[O:21])[CH2:13][C@H:12]2[O:30][CH3:31])=[O:9])=[N:5][C:4]=1[C:32]([F:35])([F:34])[F:33])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([OH:22])=[O:21])[CH2:13][C@H:12]2[O:30][CH3:31])=[O:9])=[N:5][C:4]=1[C:32]([F:34])([F:35])[F:33])[CH3:2]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC(C)(C)C)c3)C[C@H]2OC)nc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)O)c3)C[C@H]2OC)nc1C(F)(F)F
Reaction time: 5 h
Yield: 85.3 %

Procedure:
tert-Butyl cis(±)-3-(4-{[(5-ethyl-4-trifluoromethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42e) (78 mg, 0.16 mmol) was dissolved in dichloromethane (3 ml). Trifluoroacetic acid (0.75 ml) was added, followed by stirring for five hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase silica gel column chromatography (elution solvent: distilled water, acetonitrile) to obtain 60.1 mg of the title compound as a white solid (87%).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20])(OC(C)(C)C)=O.[C:21]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])C([O-])=O.Cl.[OH-].[Na+]>CCCCC.C1COCC1>[NH:13]1[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:20]=[C:6]1[C:21]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C([O-])C(=O)OCc1ccccc1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(OCc1ccccc1)c1cc2cnccc2[nH]1
Temperature: -40 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
40 ml of 1.7M tert-butyllithium in pentane are added, at −40° C. under nitrogen, to 5 g of 4-(N-Bocamino)-3-methylpyridine. After stirring for 1 hour at −40° C., the lithiated derivative thus formed is added to 12.9 g of benzyl oxalate in 100 ml of THF at −40° C. The mixture is allowed to return to 0° C., it is left stirring for 2 hours, 25 ml of 6N HCl are then added and this mixture is heated at 50° C. for one and a half hours. The pH is brought to 9 by addition of 1N NaOH, the mixture is then extracted with EtOAc and the extracts are dried and evaporated. The residue is chromatographed on silica, eluting with DCM/MeOR (100/3; v/v) to give 2.7 g of the expected compound.
Reaction SMILES: O=C(C)C[N:4]1[C:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][C:6]([NH2:28])=[N:5]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O1[CH2:46][CH2:45][CH2:44]C1>CO>[CH3:44][C:45]1[NH:28][C:6]2[N:5]([CH:46]=1)[N:4]=[CH:8][CH:7]=2
Reactant: C1CCOC1
Reactant: CC(=O)Cn1nc(N)cc1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cn2nccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-oxopropyl)-5-triphenylmethyl-aminopyrazole (0.75 g) in methanol was added conc. hydrochloric acid (0.75 ml). The mixture was stirred for 2 hours. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and ice-cold water, and the mixture was adjusted to pH 8 with sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure The residue was pulverized with diisopropyl ether to give 2-methyl-1H-imidazo[1,2-b]pyrazole.