Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])N1C1C=CC=CC=1.C(O)(=[O:28])C>Cl.O1CCOCC1>[OH:28][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:1]1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reaction time: 4 h
Yield: 55 %

Procedure:
A solution of 2 (3.11 g, 9.39 mmol) in a mixture of 6N hydrochloric acid (150 mL) and dioxane (150 mL) was heated at reflux under Ar for 18 h. Acetic acid (50 mL) was added and heating was continued for an additional 4 h. The organic solvents were removed in vacuo and the remaining aqueous was extracted with ethyl acetate (3×), washed with brine and dried with sodium sulfate (anh.). Filtration followed by removal of the solvent in vacuo gave 3 as a white solid (1.32 g, 55%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Fc1cnccc1Nn1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(ccn2Nc2ccncc2F)c1
Yield: 137.1 %

Procedure:
In a 500 ml Parr hydrogenation bottle, 10% Pd/C (1.0 g) was suspended in 50 ml ethanol, and to this was added a solution of 1-(3-fluoro-4-pyridinylamino)-5-phenylmethoxy-1H-indole (5.0 g) in 200 ml ethanol. The mixture was shaken at 50° C. under 50 psi hydrogen gas for two hours. After cooling, the mixture was filtered, and the filtrate was concentrated to give an oil (5.0 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give a crystalline solid, 3.5 g, m.p. 70°-73° C.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:20]=[C:19]([Cl:29])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:29][C:19]1[NH:20][C:21]([NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCC2)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NN=c1nc(Cl)[nH]c(NC2CCC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-[2-chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate (0.495 g, 0.96 mmol) in MeOH (10 mL) was added 4M HCl in 1,4-dioxane (10 mL). The reaction was stirred at room temperature overnight, then the solvent was evaporated, and the residue was treated with a standard K2CO3 aqueous workup to provide 2-chloro-6-(cyclobutylamino)-5-fluoro-4(1H)-pyrimidinone hydrazone as a reddish brown oil (0.225 g). LCMS: (M+H)+=232.0.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].[I-].[Na+].O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-hydroxybenzoic acid (1.38 g, 0.01 mol), 2-chloro-N,N-diethylacetamide (1.4 g, 0.01 mol) triethylamine (1.44 ml. 0.01 mol) and sodium iodide (150 mg, 0.001 mol) in N,N-dimethylformamide (6 ml) was stirred at room temperature for 18 h. Water (100 ml) was added and the mixture allowed to stand at 4° C. for 5 h. The title compound was isolated by filtration, washed with water and recrystallized from ethanol-water to give 1.8 g. Mp 148°-149° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]3[C:34]4[C:39]([CH:40]=[CH:41][C:26]2=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:21][CH:20]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]3[C:34]4[C:39]([CH:40]=[CH:41][C:26]2=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:21][CH:20]=1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccccc1C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 75.1 %

Procedure:
2-Isopropoxybenzoic acid (36 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol), the title compound (36 mg, yield 75%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: C(=O)([O-])[O-].C(=O)(O)[O-].C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:25]1[C:30]([C:31]([CH2:33]Br)=O)=[CH:29][CH:28]=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1>C(O)CCC.C(O)(C)C.C(O)C>[N+:35]([C:27]1[CH:28]=[CH:29][C:30]([C:31]2[N:14]=[C:15]3[N:19]([CH:33]=2)[C:18]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:17]=2[S:16]3)=[CH:25][CH:26]=1)([O-:37])=[O:36]
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCO
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Temperature: 112.5 °C

Procedure:
Alternatively, the reaction may be carried out in the presence of a base, for example, in the presence of one or more carbonate or bicarbonate salt. For example, sodium bicarbonate is added to a mixture of 2-amino-6-hydroxybenzothiazole and 2-bromo-4-nitroacetophenone in a suitable solvent such as ethanol, isopropanol or n-butanol, and the resulting mixture is stirred at a suitable temperature, for example, to reflux and maintained at reflux (110-115° C.) for 2-3 h or until the reaction is substantially complete.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[S:24][C:25]([CH:28]=O)=[CH:26][N:27]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.O1CCCC1.CO>C(Cl)Cl>[CH:1]1([NH:7][CH2:28][C:25]2[S:24][C:23]([NH:22][C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]4)=[C:10]([O:9][CH3:8])[CH:11]=3)=[N:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Nc2ncc(CNC3CCCCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 19 mg (0.19 mmol) cyclohexylamine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (1 ml), methanol (1 ml) and methylene chloride (1 ml). The reaction was not complete and the same amount of reagent was added like in example 57. Only the imine was formed. Therefore the crude product was dissolved in methanol (1 ml) and 8.6 mg sodium borohydride was added and the reaction stirred for 4 hours at room temperature. After workup the crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 16 mg (21%) of (5-cyclohexylaminomethyl-thiazol-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow oil. MS ISP (m/e): 398.3 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.62 (s, 1H), 7.25 (s, 1H), 7.16 (d, 1H), 7.10 (s, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 3.94 (s, 2H), 3.85 (s, 3H), 2.54 (m, 1H), 2.30 (s, 3H), 1.93 (m, 2H), 1.72 (m, 2H), 1.64 (m, 1H), 1.28-1.09 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:35][C:36](N(C)C)=[O:37]>>[C:36]([N:29]1[CH2:28][CH2:27][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=3)[CH:15]=4)[CH:17]=2)[CH2:31][CH2:30]1)(=[O:37])[CH3:35]
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 55 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(4-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 30 mg (55%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1 H) 7.81 (s, 1 H) 7.77 (d, 1 H) 7.62 (d, 1 H) 7.32-7.40 (m, 2 H) 7.19 (d, 1 H) 7.03-7.10 (m, 2 H) 6.55 (s, 1 H) 5.61 (s, 2 H) 4.63 (d, 1 H) 4.00 (d, 1 H) 3.45 (tt, 1 H) 3.25 (td, 1 H) 2.75 (td, 1 H) 2.07-2.18 (m, 5 H) 1.62-1.72 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][S:9](O)(=[O:11])=[O:10].S(Cl)(Cl)=O>S(=O)(=O)(O)N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:9]([Cl:8])(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccccc1
Agent: NS(=O)(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
112.6 g (1.0 mol) of chlorobenzene are added dropwise at 70° C. over a period of 1 hour to 122 g (1.05 mol) of chlorosulfonic acid. The mixture is then stirred at this temperature for 15 minutes. 1 g of sulfamic acid is then added and 180 g (1.5 mol) of thionyl chloride are added dropwise at 70° C. in the course of 2 hours. Working up is carried out as described in Example 1. 228.3 g of moist 4-chlorobenzenesulfonyl chloride having a water content of 12% are obtained. This corresponds to 200.9 g of 4chlorobenzenesulfonyl chloride (94.4% of theory), calculated as dry material, having a purity of 95%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Yield: 42.5 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (95 mg, 0.41 mmol) and potassium carbonate (75 mg, 0.54 mmol) in anhydrous DCM (1.5 ml) was added dropwise phenyl chloroformate (0.16 ml, 1.24 mmol) as a solution in DCM (1 ml). The crude was purified by silica gel chromatography (DCM/EtOAc 7-60%) to afford phenyl 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (61 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 2.63 (s, 3H), 6.47 (s, 1H), 6.83 (d, J=8 Hz, 1H), 6.91-6.93 (m, 3H), 7.12 (s, 1H), 7.21-7.40 (m, 2H), 7.78 (d, J=8 Hz, 1H), 8.68 (d, J=2 Hz, 1H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH:25]([N:27]1C(=O)C2=CC=CC=C2C1=O)[CH3:26].C(Cl)(Cl)Cl>C(O)C.O.NN>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH:25]([NH2:27])[CH3:26]
Reactant: CC(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(N)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Yield: 84.3 %

Procedure:
In a solution of 0.40 g of N-[1-[2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl]ethyl]phthalimide in 10 mL of ethanol, 1.0 mL of 80% hydrazine monohydrate aqueous solution was added, and stirred under reflux with heating for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 20 mL of chloroform was added therein and insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The procedure comprising adding 20 mL of chloroform in the residue, filtering off insoluble material and distilling off the solvent under reduced pressure was repeated twice to obtain 0.26 g of the aimed product as yellow resinous substance.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:52]=1)([CH3:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:45]([C:48]1[S:49][CH:50]=[C:51](/[CH:53]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:52]=1)([CH3:47])[CH3:46]
Reactant: CC(C)c1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 11.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.60 g), [(2-isopropyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.7 g), potassium carbonate (0.57 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 17 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:4, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (0.22 g, yield 11%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][NH:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>>[CH3:24][NH:25][C:26](=[O:31])[CH2:27][C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CNC(=O)CC(=O)O
Product: CNC(=O)CC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-(methylamino)-3-oxopropanoic acid to yield (3aR,4S,7aR)-methyl 4-(3-(methylamino)-3-oxopropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=1.01 min; UPLC Method I
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(NC(C)=O)nc2C)cc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A stirred solution of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (Description 7 in EP 97/17351, 300 mg, 1.2 mmole) and pyridine (0.16 ml, 2.0 mmole) in DCM (35 ml) at 0° C. under argon was treated with acetyl chloride (120 mg, 1.5 mmole) and allowed to warm to room temperature over 1 h. Additional acetyl chloride (120 mg) was added, the mixture maintained at room temperature for a further 1 h, then washed with 10% Na2CO3 solution, dried (Na2SO4) and concentrated under vacuum to afford the title compound as a white solid (344 mg, 98%).
Reaction SMILES: [NH2-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>CN(C)C1C=CC=CC=1>[NH2:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: [NH2-]
Reactant: CC(C)(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 55.2 %

Procedure:
To 790 mg of sodium amide were added 20 mL of N,N-dimethylaniline and 2.74 g of 4-t-butyl pyridine at rt. The mixture was stirred at 150° C. for 6 h. During this period, 3 more portions of sodium amide (790 mg each) were added. The reaction was cooled down to rt. The mixture was partitioned between ethyl acetate and water. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes followed by 100% ethyl acetate to give 1.68 g of the title compound as a solid:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10](=[O:15])[N:9]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[ClH:29]>O1CCOCC1>[ClH:29].[CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10](=[O:15])[N:9]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3cc(C4CC4)cc(F)c3c2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2c(F)cc(C3CC3)cc2ccn1[C@@H]1CCCNC1

Procedure:
Compound 57 was treated with 4N HCl in dioxane (20 mL) at RT for 1 h. The mixture was concentrated in vacuo and the solid residue was triturated with MTBE (40 mL) at RT overnight. The solid was filtered, washed with MTBE and dried in vacuo to give (R)-6-cyclopropyl-8-fluoro-2-(piperidin-3-yl)isoquinolin-1(2H)-one hydrochloride (59) (51 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:11]1([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.8 mmol of 4-benzoxazol-2-yl-piperazine-1-carboxylic acid tert.-butyl ester were treated with 30 ml of a dioxane, saturated with gaseous hydrochloric acid. The heterogenous mixture was stirred at room temperature for 1 hour, before evaporation of the solvent. This yielded the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: ClCCN1CCCCC1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CCN2CCCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=610.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:42].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:11][C:10]1[CH:12]=[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:14]=[CH:15][C:9]=1[C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:24]([CH3:42])[C:25]([C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: COc1ccc(-c2ccc(N3CCOCC3)cc2N)cn1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline (61.1 mg, 0.21 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (53.9 mg, 0.18 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (17.2 mg, 0.036 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.1 mg, 7.75 mmol), and sodium tert-butoxide (44.4 mg, 0.46 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 20 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (10-30% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield an orange solid as 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1H, d, J=5.1 Hz), 7.99 (1H, d, J=2.2 Hz), 7.65 (1H, m), 7.58 (4H, m), 7.14 (1H, d, J=8.4 Hz), 6.80 (1H, d, J=7.8 Hz), 6.62 (2H, d, J=8.6 Hz), 3.84 (7H, m), 3.18 (4H, m), 2.48 (3H, s), 2.06 (3H, s). Mass Spectrum (pos.) m/e: 554.2 (M+1).