Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:42](O)(=[O:45])[CH2:43][CH3:44].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(N(CC)CC)C>[C:4]1([C@H:3]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24]([C:26]2[C:27]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:17]=[CH:16]3)=[O:12])[CH2:2][NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC(=O)O
Reactant: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (N, 30 mg, 0.05 mM), proprionic acid (0.075 mM), EDC (14 mg, 0.075 mM), HOBT (11 mg, 0.075 mM), and triethylamine (0.03 mL, 0.21 mM) were taken up in CH2Cl2 (1 mL) and stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by flash chromatography (silica gel) eluting with EtOAc/hexanes. HPLC retention time, 2.87 min; ESMS (m+1), 611; calc. Mw, 610
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:28](=[O:30])[CH3:29])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Product: Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 6.4 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 65 ml of acetic anhydride and 0.7 ml of pyridine is stirred at 110° C. for 3 hours. After the reaction is completed, the reaction mixture is evaporated to remove solvent. The residue is converted to its hydrochloride and recrystallized from a mixture of acetone and ethanol. 4.7 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCCOC1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCCOC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9H-purine-2,6-diamine trifluoroacetate (400 mg) in N,N-dimethylformamide (6.90 ml) at room temperature was added potassium carbonate (610 mg) and the reaction stirred at 60° C. for 90 minutes. The reaction mixture was cooled to room temperature and tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (236 mg) was added. Stirring was continued at 50° C. for 20 hours. The reaction temperature was increased to 90° C. and stirring continued. The reaction was cooled and taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-50%) to afford the title compound as a colourless oil (198 mg, 88% pure).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([O:17]C)=[O:16].CO.O.[OH-].[Li+]>C1COCC1>[N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1nc2n(n1)-c1ccccc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2n(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ester 86 (0.166 g, 0.677 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (31.2 mL), treated with 4 N aqueous lithium hydroxide (1.32 mL), and the mixture was stirred for 30 min at 25° C. (FIG. 18). The reaction was quenched with 1 N aq. HCl (20 mL) and the solution was extracted three times with 20 mL EtOAc. The combined organic extracts were dried with sodium sulfate, and concentrated to give crude 4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid which was taken forward to the next step. LRMS m/z Calcd. for C12H9N3O3: 231.06439, found: 232.1 [M+1].
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:20])[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)C.[NH3:31]>C(O)C>[NH2:31][N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:20])[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1
Reactant: CCON=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)OCC)cc1
Reactant: N
Solvent: CCO
Product: CCOC(=O)CNC(=O)N(Cc1ccc(C=NN)cc1)OCc1ccccc1
Reaction time: 24 h

Procedure:
2.83 g (6.84 mmol) of ethyl (3-(4-(ethoxyiminomethyl)benzyl)-3-benzyloxyureido)acetate are dissolved in 100 ml of ethanol and treated with 6.74 ml (6.84 mmol) of ethanolic ammonia solution. After 24 h at room temperature, the solvent is removed in vacuo and the residue is recrystallized from ethyl acetate/ether.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[O:9])[CH2:7]Br.CN(C)[CH:17]=[O:18].N1(C2[CH2:30][CH2:29][S:28][CH2:27][CH:26]=2)CCCC1>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[O:9])[CH2:7][CH:26]1[C:17](=[O:18])[CH2:30][CH2:29][S:28][CH2:27]1
Reactant: C1=C(N2CCCC2)CCSC1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Solvent: O
Product: O=C(CC1CSCCC1=O)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 32.6 g of m-trifluoromethylphenacyl bromide in 10 ml. of dimethylformamide is added dropwise to a stirred solution of 20 g (0.12 mole of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)] and 100 ml. of dimethylformamide. After 2 hours, the mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate, and concentrated to an oil. The oil is chromatographed on silica gel with benzene and chloroform mixtures to give 2,3,5,6-tetrahydro-3-(3-trifluoromethylphenacyl)thiopyran-4-one as an oil. Infrared and nuclear magnetic resonance spectra are consistent with the assigned structure.
Reaction SMILES: [H][H].[NH3:3].C([O:8][C:9](=[O:40])[CH2:10][O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]2[O:23]C(=O)C)=[C:14](Cl)[N:13]=1)(C)(C)C>>[C:9]([CH2:10][O:11][C:12]1[N:13]=[C:14]([NH2:3])[C:15]2[N:16]=[CH:17][N:18]([C:19]=2[N:20]=1)[C@@H:21]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]1[OH:23])([OH:8])=[O:40]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCC(=O)OC(C)(C)C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Reactant: [H][H]
Product: Nc1nc(OCC(=O)O)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70 %

Procedure:
A compound having a structure of the above formula was prepared where the substituents R1 and R2 are hydrogen and R3 is —CH2COOH. The compound (C12H15N5O7) was prepared by reaction of ammonia with (6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuran-osyl)purin-2-yl)oxyacetic acid tert-butyl ester (Example 6) as described in Example 2, Step E. The final product was isolated in 70% yield as a solid with a melting point of 200-203° C. 1H-NMR (DMSO-d6): δ 3.4 (m, 1H); 3.55 (m, 1H); 3.91 (m, 1H); 4.11 (m, 1H); 4.56 (m, 1H); 4.74 (bs, 1H); 4.78 (s, 2H); 5.3 (bs, 2H); 5.75 (d, 1H, J=6); 7.36 (bs, 2H); 8.15 (s, 1H); 12.6 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.N.[H][H].C[OH:32]>[Ni]>[OH2:32].[NH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:17]3[C:12]([N:11]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:20][CH2:21]1
Reactant: CO
Reactant: N#CCN1CCC(Nc2nc3ncccc3n2Cc2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NCCN1CCC(Nc2nc3ncccc3n2Cc2ccc(F)cc2)CC1
Product: O
Yield: 78 %

Procedure:
A mixture of 12 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile and 200 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 10 parts (78%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-imidazo[4,5-b]pyridin-2-amine monohydrate; mp. 116.9° C. (intermediate 109).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:15]=[S:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:25]
Reactant: N=S(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N=S(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.2 g (0.19 mol) of triethylamine in 50 ml of methylene chloride is added dropwise at room temperature, whilst stirring to a solution of 19 g (0.095 mol) of S,S-diphenylsulphilimine [compare Furukawa et al., Univ. Osaka: Tetrahedron Letters 1972, 1619-1622; Tamura et al., Univ. Osaka: Tetrahedron Letters 1972, 4137-4140] in 120 ml of methylene chloride and subsequently, whilst cooling slightly, a solution of 12.3 g (0.11 mol) of chloroacetyl chloride in 80 ml of methylene chloride is added dropwise. The mixture is stirred overnight at room temperature, the solvent is stripped off in vacuo, the residue is taken up in methylene chloride and the organic phase is washed with water until neutral. The product is then dried over sodium sulphate and the solution is evaporated in vacuo. N-(Chloroacetyl)-S,S-diphenylsulphilimine is obtained as an oily residue and is further processed as the crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].C1COCC1.[OH-].[NH4+:20]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][NH:20][C:5]2=[O:6]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCc2c(Br)cccc21
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (27 mmol) in THF (100 mmol) was added ammonium hydroxide (9 mL) dropwise at rt. The reaction mixture was allowed to stir overnight and then diluted with 30 mL of water. The solution was extracted with DCM, dried over Na2SO4, filtered and concentrated to give 4-bromoisoindolin-1-one (5.20 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:23]4[CH2:24][CH2:25][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([OH:19])[CH2:21][CH2:22]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 32 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-hydroxy-4phenylpiperidine, the title compound hydrochloride salt was obtained in 32% yield as a white powder, mp 260°-261° C. elemental
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[N:28]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:22].[CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:28]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Oc3ccccc3Cl)cc2OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)CCc1csc(Nc2ncc(Oc3ccccc3Cl)cc2OCc2ccccc2)n1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 148.8 %

Procedure:
A mixture of methyl 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (Example 131; 0.315 g, 0.635 mmol), 1M aqueous sodium hydroxide (0.953 ml, 0.953 mmol), and methanol (6 mL) was heated at 65° C. for one hour. The reaction mixture was then cooled and partitioned between chloroform and saturated ammonium chloride, and the aqueous layer was extracted twice with chloroform. The combined organic layers were washed with brine, dried, and concentrated. The residue was dissolved in THF (2 mL) and ether (2 mL, and 1N HCl in ether (1.5 mL) was added. The mixture was stirred 5 minutes, and then hexanes (3 mL) were added. The solids were isolated by filtration to afford 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoic acid hydrochloride (0.245 g, 74.4% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.64 (t, 2H), 2.87 (t, 3H), 5.32 (s, 2H), 6.81 (s, 1H), 6.99 (d, 1H), 7.21 (t, 1H), 7.31-7.43 (m, 4H), 7.47 (d, 1H), 7.55-7.66 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Tert-butyl 4-hydroxyphenylcarbamate (3.63 g, 17.4 mmol) was dissolved in dry DMF (150 mL). Potassium tert-butoxide (2.62 g, 23.4 mmol) was added and the stirring was continued for 30 minutes at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 85° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (800 ml) and washed with water (1×800 ml) and brine (2×800 ml). The organic layer was dried with magnesium sulphate and evaporated. The crude was chromatographed over silica (eluant ethyl acetate: cyclohexane 1:2) to yield 4.0 g (63 yield) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3cnc(N4CCOCC4)nc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3cnc(N4CCOCC4)nc3)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde (159 mg, 0.464 mmol) was dissolved in acetonitrile (6 mL) and warm tert-butanol (6 mL) and treated with 2-methyl-2-butene. The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (630 mg, 9.27 mmol) and sodium phosphate monobasic dihydrate (1.45 g, 9.30 mmol) in water (5 mL) via addition funnel. The mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove the organics and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried and concentrated in vacuo to give a crude, which was purified by prep-HPLC to give 6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carboxylic acid (67.6 mg, 40.60% yield) as a white solid. MS (ES+) 359.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 12.03 (s, 1H), 8.49 (m, 2H), 8.12 (m, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 3.78 (m, 4H), 3.70 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][O:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[N:3]=1.ClCCl.Cl.C(OCC)(=O)C>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][O:22][C:23](=[O:33])[CH2:24][NH2:25])=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CN)cc2)n1
Yield: 47.6 %

Procedure:
A mixture of 2-tert-butoxycarbonylamino-acetic acid 4-[4-amino-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazin-2yl-amino]-benzyl ester (1.0 g, 2 mmol), dichloromethane (20 ml), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 ml) was stirred for 12 hours. The reaction mixture was poured into ethyl acetate (100 ml). The solid filtered and dried under reduced pressure to provide the hydrochloride salt of the title compound (0.38 g, 84% yield). 1H NMR (CD3OD) δ7.75-8 (br s, 2H), 7.74 (s, 1H), 7.56-7.43 (m, 6H), 5.36 (s, 2H) 3.67 (s, 2H) 2.58 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:36]([C:37]1[O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:9]=2[N:8]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2c(OC)cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
Triethylamine (5.30 ml) was added to a suspension of 2-amino-3-methoxybenzoic acid (3.00 g) in methylene chloride (30 ml). The mixture was cooled with ice and stearoyl chloride (5.44 g) was dropwise added thereto. The reaction mixture was stirred for 2.5 hours at room temperature and then cooled with ice. Then, triethylamine (2.80 ml) and ethyl chlorocarbonate (1.88 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 150 g, chloroform-hexane), thereby yielding 3.73 g of the aimed compound as colorless solid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][C:11]([CH3:13])=[O:12]>>[C:11]([C:13]1[CH:8]=[CH:9][C:4]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][C:6]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:12])[CH3:10]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2)cc1-c1ccccc1

Procedure:
Nitrobenzene is stripped with steam and the solid residue is dissolved into acetone. After filtration and the acetone evaporation, 400 g of crude product is obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:19][C:2]([F:1])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:27](=[O:29])[CH3:28])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 2-[2-(trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl]ethanamine (70 mg, 0.26 mmol) and triethylamine (72 μL, 0.52 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (22 μL, 0.31 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) and recrystallization (ethyl acetate/hexane) to give the title compound (61.8 mg, yield 76%).