Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N+:27]([O-:29])=[O:28])=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1cc([N+](=O)[O-])c2ccccc2c1NC(=O)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 1,2-diethoxalylaminonaphthalene (10.8 g, 0.03 mol) in 150 ml of acetic acid was treated dropwise with nitric acid (1.24 ml, 0.03 mol, d 1.52) and stirred over night at room temperature. Then an additional amount of nitric acid (2.0 ml, d 1.52) was added dropwise and the mixture was stirred for 17 h at room temperature. The mixture was poured into 200 ml of ice/water and the resulting precipitate was isolated by filtration and washed with water, a small amount of cold ethanol and ether affording 3.3 g (27%) of pure product,
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCCCC>C(OCC)C>[OH:21][C:15]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCCCC2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
A solution of n-butyllithium (1.6M in hexanes, 150 ml) was added dropwise over 1 hour to a mechanically stirred solution of 5-bromo-2-methoxypyridine (39.3 g) in 800 ml of diethyl ether at -40° C. The resulting slurry was stirred at -40° C. to -45° C. for 45 minutes, and then cyclohexanone (23.5 g) in 50 ml of diethyl ether was added dropwise over 1 hour. The mixture was allowed to warm to 0° C. over about 1 hour, and then the reaction was quenched with saturated ammonium chloride solution. The layers were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to yield a semi-solid material. Trituration with pentane provided 29.0 g of product as a powder. Recrystallization of 8 g of the product gave 6.2 g of plates, m.p. 74°-75° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:42])[O:37][CH2:38][CH2:39][O:40][CH3:41].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:36](=[O:42])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: COCCOC(=O)Cl
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and 2-methoxyethyl carbonochloridate (99 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:17]4[CH2:18][CH2:19][N:14]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:15][CH2:16]4)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2oc3ccc(CC(=O)O)cc3c2SC)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2oc3ccc(CC(=O)N4CCN(c5ccccc5)CC4)cc3c2SC)cc1OC
Reaction time: 16 h
Yield: 554 %

Procedure:
Triethylamine and 12.992 mg of 1-phenyl-piperazine (0.080 mM) were added to the solution containing 35 mg of 3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid (35a; 0.068 mM) dissolved in 2 ml of dichloromethane. The reaction mixture was stirred for 16 hours and the remaining solvent was removed. The remaining residue was purified with Silica gel column chromatography with a mobile phase (dichloromethane:methanol=20:1) to obtain white solid type of 2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone (37a; 223 mg).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 4-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 55 mg (52.8% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]3)[NH:10][C:6]=2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:10]1[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3](=[O:27])[N:2]([CH3:1])[C:7]=2[CH:8]=[C:9]1[N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1
Reactant: Clc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O

Procedure:
A solution of tert-butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)piperidin-3-yl]carbamate (60 mg), 2-chlorobenzyl bromide (32 μl) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure and purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (10 mg) as a white amorphous substance.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:45][C:46]1[N:50]([CH3:51])[C:49]([CH3:52])=[N:48][N:47]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]3[N:50]([CH3:51])[C:49]([CH3:52])=[N:48][N:47]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1nnc(CCl)n1C
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cc1nnc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 384.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2csc(N3CCOCC3)n2)c(OC)c1)OCC
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 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 to give diethyl (E)-2-{3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.36 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:26]COCC>C1COCC1>[C:1]([N:8]([C@H:9]([C:20]#[CH:21])[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH3:11])[CH3:26])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C#C[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(2R,3R)-3-(N-Boc-N-methylamino)-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was synthesized according to Method Y above by the treatment of (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and MeI (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after silica gel column chromatography with a 0-10% Et2O in hexanes gradient. (Yield 370 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)s1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(Br)s1)c1cccc(Cl)c1

Procedure:
In analogy to example 4, step 1, 1-(5-bromo-2-thienyl)methanamine was reacted with 3-chlorobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-(5-bromo-thiophen-2-ylmethyl)-3-chloro-benzenesulfonamide as a colorless solid. MS: 363.9 ([M−H]−)
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][CH:16]1[C:33](=[O:50])[NH:34][C:35]1([C:40]([NH:42][S:43]([O:46][CH:47]2[CH2:49][CH2:48]2)(=[O:45])=[O:44])=[O:41])[CH2:37][CH:36]1[CH:38]=[CH2:39])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCOC(C)=O.CCO>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][CH:16]1[C:33](=[O:50])[NH:34][C:35]1([C:40]([NH:42][S:43]([O:46][CH:47]2[CH2:49][CH2:48]2)(=[O:44])=[O:45])=[O:41])[CH2:37][CH:36]1[CH2:38][CH3:39])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the trifluoroacetate salt of 2-(1-cyclopropoxysulfonylaminocarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (181 mg, 0.253 mmol) Rh/AlO3 (37.2 mg, 5 wt %) was added and the mixture was suspended in EtOAc (4.5 mL) and EtOH (1.0 mL). The reaction flask was flushed with H2 gas and the reaction was allowed to stir at room temperature under a hydrogen atmosphere for 3 h. The reaction was filtered through a syringe tip filter (0.45 μM) and washed with ethanol. The filtrate was concentrated and then filtered through a C-18 RP SPE column (Phenomenex Strata, 1 g) and washed with methanol. The filtrate was concentrated and purified on silica (12 g, 0-7% MeOH/CH2Cl2) to give 2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (151 mg, 83%). LCMS found 619.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:16][CH:17]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=1[Cl:27])[CH3:18].[CH3:28][P:29](Cl)([CH3:31])=[O:30].C(N(CC)CC)C>ClCCl>[Cl:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[CH:17]([O:16][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][P:29]([CH3:31])([CH3:28])=[O:30])=[CH:12][CH:13]=2)[CH:4]=1)[CH3:18]
Reactant: CC(Oc1cc(-c2ccc(CO)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CP(C)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-c2ccc(COP(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
a mixture of [4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]phenyl]methanol (15 mg, 0.037 mmol), dimethylphosphoryl chloride (50 mg, 0.45 mmol), and triethylamine (0.5 mL) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was purified by HPLC (water/methanol, 10˜100%) to give the title compound (2 mg, 11%). ESMS: m/z 483 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:23])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O.C1C[O:31][CH2:30]C1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:23])=[C:21]3[NH:22][C:30]2=[O:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (91.0 g) in THF (850 mL) was added N,N′-carbonylimidazol (90.8 g) at room temperature. The mixture was stirred at room temperature for 17 h. To the mixture was added 1 N NaOH (300 mL) over 10 min in ice bath, and the mixture was stirred for 15 min. To the mixture was added 1 N HCl (460 mL) under ice cooling, and then the mixture was stirred for 15 min. To the mixture was added water (90 mL) at room temperature, and then the mixture was stirred for 20 min. The precipitate was collected by filtration, washed with water (1.3 L), and dried in air blowing for 30 min. The precipitate was washed with IPE (1.5 L) and dried in vacuo at 55° C. for 2.5 h. The precipitate was suspended in IPE (500 mL), and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration, washed with IPE (500 mL), and dried in vacuo to give 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 g) as a purple solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>C(O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([CH:2]=[C:3]([CH2:4][CH3:5])[N:7]=2)[CH:10]=1
Reactant: CCC(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
5.0 g of 1-bromo-2-butanone was dissolved in 80 ml of ethanol, 5.71 g of 2-amino-5-bromopyridine was added, and the mixture was stirred all night by heating under reflux. After cooling down to room temperature, the solvents were distilled outunder reduced pressure, and ethyl acetated followed by saturated sodium bicarbonate aqueous solution were added. After drying organic layer with anhydrous sodium sulfate, the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer silicagel chromatography (hexane:ethyl acetate=75:25), to obtain 4.82 g of the above compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)CC)C.CN1CCCC1=O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[N:23][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: O=C1CNCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCNC(=O)C3)cc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 (55.0 mg, 0.166 mmol), piperazin-2-one (0.110 g, 1.10 mmol) and triethylamine (0.275 mL, 1.97 mmol) in N-methylpyrrolidinone (3.00 mL, 31.1 mmol) was heated at 150° C. for 2d. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water and brine. The organic layer was dried Na2SO4, concentrated to give 325, analyzed by rHPLC. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.63-4.30 (m, 4H), 4.06 (d, J=8.0 Hz, 2H), 3.81-3.63 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ncccc1O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2ncccc2O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30.5 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.468 g of 2-amino-3-hydroxypyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was poured into a water and ice mixture. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over MgSO4 and then evaporated to dryness under vacuum. 0.15 g of 2-[(4-nitrophenyl)amino]pyrid-3-ol (3) was obtained.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.[CH2:16]([CH:18]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([NH:32][C@@H:33]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:34](O)=[O:35])=[O:31])=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:41][C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[CH2:19][CH3:20])[CH3:17].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:5][C:34]([C@@H:33]([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]3[N:21]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[C:22]([CH2:41][C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)=[N:23][C:24]=3[CH:29]=2)=[O:31])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:35])[CH2:4][CH2:3][CH2:2]1
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)O)ccc21
Reactant: NC1CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CCC3)ccc21
Temperature: 25 °C
Yield: 65.7 %

Procedure:
Into a reaction vial were placed 10 mg of cyclobutylamine, 20 mg of HOAt, 53 mg of (S)-2-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid. Then 0.11 ml DIPEA in 1 ml DMF were added, followed by 67 mg PyBrOP in 0.5 ml DMF. The reaction was shaken at RT over night, then filtered and purified by HPLC to yield 39 mg (74%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyclobutylcarbamoyl-3-methyl-butyl)-amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:39][CH2:40][CH2:41][O:42][CH3:43]>COCCOC.CO.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:5]=3)[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.560 g, 0.95 mmol) and 10% Pd/C (ca. 0.1 g) in DME (100 mL) and MeOH (100 mL) was hydrogenated under a balloon of H2 at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to give tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate as an off white solid (0.510 g, 0.92 mmol, 97%). HPLC retention time 5.62 mins.