Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:22]([CH3:21])[C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:17]([F:20])([F:19])[F:18])=[C:8]([O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:13]=1)=[O:16])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=361.5 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[C:10](Cl)=[N:9][N:8]=[N:7]1)C.NC(N)=[S:15].O.Cl>C(O)C>[SH:15][C:10]1[N:6]([CH2:5][C:4]([OH:3])=[O:12])[N:7]=[N:8][N:9]=1
Reactant: CCOC(=O)Cn1nnnc1Cl
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1nnnc1S

Procedure:
In a 500 ml round flash equipped with agitator, relux condenser, thermometer and a dropping funnel a mixture of 100 g (0.52 mol) 5-Chloro-1H-tetrazole-1-acetic acid ethyl ester, 44 g (0,57 Mol) thiourea, 210 g water and 25 g of 38 wt.% aqueous hydrochloric acid was heated to reflux for 6 hours, while the ethanol formed during the reaction was distilled off. For working up purpose, the residue was extracted with methyl isobutyl ketone. After evaporation of the ketone 57.9 g=69% of the theory of a white crystalline solid (melting point 173° C.) of 5-Mercapto-1H-tetrazole-1-acetic acid was obtained (purity 99%).
Reaction SMILES: [CH:1]1([C:10](O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[C:16]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][C:18]2[O:22][CH2:21][CH2:20][C:19]=2[CH:23]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH3:13][O:14][C:15]1[C:16]([N:24]2[CH2:25][CH2:26][N:27]([CH2:10][CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:28][CH2:29]2)=[CH:17][C:18]2[O:22][CH2:21][CH2:20][C:19]=2[CH:23]=1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: O=C(O)C1CCc2ccccc21
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3CCc4ccccc43)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from indan-1-ylcarboxylic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 195°-197° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([OH:12])[CH2:10][CH3:11].[C:20]1([CH2:26][CH2:27][CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([OH:12])[CH2:10][CH3:11]
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(O)(c1ccc(OCCCc2ccccc2)cc1)c1ccccc1OC

Procedure:
6.45 g. of 1-(2-methoxyphenyl)-1-(4-hydroxyphenyl)-propan-1-ol, 5.5 g. of 3-phenylpropyl bromide, 6.5 g. of anhydrous potassium carbonate, 0.5 g. of potassium iodide and 65 ml. of dry acetone are slightly boiled for 15 hours, with stirring. After cooling, acetone is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The organic phase is washed to neutral with water, a 5% aqueous sodium hydroxide solution and again water. After drying over anhydrous magnesium sulfate the solution is evaporated in vacuo. The residue is crystallized from n-hexane to yield 7.8 g. of the named compound, melting at 75°-76° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[N:17]=[C:16]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[CH2:37][OH:38])[CH:14]=2)[N:9]=1.CO>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:38][CH2:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:7])[N:17]=[C:16]2[C:18]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
20 μl of dimethylcarbamoyl chloride are added to a solution of 100 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide (DMF), and the mixture is heated at 80° C. for 18 h. After 18 h, 10 ml of methanol are added, the mixture is evaporated to dryness in vacuo and purified by normal-phase chromatography.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+]>>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CCCCCCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCOc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Heptyloxy-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C36H36O6 [M+Na]+: 467, [M+H]+: 445.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].N1CCCCC1>C(O)C>[C:9]([C:11](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: N#CCC(=O)O
Reactant: O=Cc1cccnc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1cccnc1)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A mixture of 3.8 g of 3-pyridinecarbaldehyde, 3.0 g of cyanoacetic acid, 3.0 g of piperidine, and 30 ml of ethanol is stirred at 100° C. for 4 hours. The reaction mixture is concentrated, and 20 ml of water is added. The mixture is adjusted to pH 4.5 with 10% hydrochloric acid. The resulting precipitate is collected and recrystallized from ethanol to give 3.8 g of the title compound, m.p. 223°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[NH2:27].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH:23]2[CH2:24][CH2:25][CH2:26][CH:22]2[CH3:21])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCCC1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCCC2C)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 9.32 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 30 ml of abs. DMF was added 16.47 g of potassium carbonate, followed by 5.00 g of 2-methyl-cyclopentylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 5 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 12.74 g (100%) of 4-(2-Methyl-cyclopentylamino)-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[C:13]([CH3:19])([CH3:18])[CH:14]=[C:15]([CH3:17])[O:16][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][OH:25]>C1(C)C=CC=CC=1>[CH3:24][O:25][C:15]1([CH3:17])[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]2[CH:20]=[CH:21][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=3)=[CH:10][C:11]=2[O:16]1
Reactant: CO
Reactant: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Solvent: Cc1ccccc1
Product: COC1(C)CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Reaction time: 4.5 h
Yield: 90 %

Procedure:
A mixture of the 7-(4-nitrophenoxy)-2,4,4-trimethyl-4H-1-benzopyran obtained in Referential Example 43, 66 ml of methanol, 0.7 g of Amberlyst-15 and 6 ml of toluene was stirred for 4.5 hours, and Amberlyst-15 was separated by filtration. The filtrate was concentrated, and 30 ml of methanol was added. Crystals that precipitated were collected by filtration, washed with 50 ml of methanol, and dried to give 6.7 g (90%) of the desired product as a white powder (melting point 125° C.).
Reaction SMILES: [Cl:1][CH:2]([C:10](=O)[CH3:11])[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].Cl.[NH2:14]O.O.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[O:9][N:14]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A solution of ethyl 3-chloro-2,4-dioxovalerate (3.0 g, 15.6 mmol) and hydroxylamine hydrochloride (1.08 g, 15.6 mmol) in a mixuture of 1.5 mL of H2O and 1 mL of CH3OH was heated to reflux. After four hours TLC analysis indicated that all of the starting material had been consumed. Sodium hydroxide (0.31 g, 7.8 mmol) was added to the hot solution. After four hours the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in a 1:1 mixture to ethyl acetate/H2O. The aqueous layer was made basic with 2N NaOH and separated. The aqueous layer was then acidified with 2M HCl and extracted with ethyl acetate (125 mL). The ethyl acetate extract was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 600 mg (24% yield) of the desired product a gummy tan solid: 1H NMR (CDCl3) 67 8.8 (bs, 1H), 2.3 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[C:33]([Cl:38])=[C:32]([Cl:39])[CH:31]=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[CH:31][C:32]([Cl:39])=[C:33]([Cl:38])[C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Reactant: Nc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 24 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc and yielded 0.16 g of impure product. Then, crystallization from EtOAc/heptane gave 90 mg (37%) of a white solid; mp 208.5-210.0° C.; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (m, 3H), 7.07 (m, 1H), 5.08 (br s, 2H), 3.63 (m, 4H), 3.40 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 3275, 1693, 1671, 1602, 1554, 1449, 1409, 1365, 1319, 1312, 1302, 1254, 1166, 1113, 762 cm−1; MS (EI) m/z 487 (M+), 346, 345, 105, 94, 92, 76, 65, 62, 56, 52; MS (FAB) m/z 488 (M+H+), 488, 487, 434, 433, 432, 431, 388, 57, 42, 41; HRMS (EI) calcd for C25H27Cl2N3O3 487 1429, found 487.1441; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.41; H, 5.70; N, 8.48.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:24]1[C:25]2[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1>CC(O)C.C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[N:33][C:25]2[C:24]([NH:1][C:2]3[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]4([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]4)[CH:7]=3)=[N:29][CH:28]=[N:27][C:26]=2[CH:30]=1
Reactant: Clc1cnc2c(Cl)ncnc2c1
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cc(Cl)cnc23)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Temperature: 100 °C
Yield: 50 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.044 g, 0.136 mmol) and 4,7-dichloropyrido[3,2-d]pyrimidine (0.030 g, 0.150 mmol) in iPrOH (2 mL) was added a catalytic amount of concentrated H2 SO4 and the resulting mixture was heated in microwave at 100° C. for 45 min. The mixture was diluted with DCM, washed with 1 N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM to afford a light brown solid as (4S,6S)-4-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.033 g, 0.068 mmol, 49.8% yield). MS m/z=486.9 [M+H]+. Calculated for C20H16ClF5N6O: 486.10.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH2:35])=[CH:28][CH:27]=1>O1CCOCC1.CC(N(C)C)=O>[I:25][C:26]1[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]([NH:35][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Yield: 70.6 %

Procedure:
4.0M HCl in Dioxane (0.37 ml) was added to a stirred suspension of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (500 mg) and 7-iodo-1,3-benzodioxol-4-amine (0.39 g) in DMA (1 ml). The resultant mixture was stirred and heated to 80° C. for 10 mins. A grey precipitate was formed which was filtered and washed with further DMA followed by diethyl ether and dried to give N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine as a beige solid (0.59 g); NMR Spectrum: (DMSOd6) 2.29-2.37 (m, 2H); 3.03-3.14 (m, 2H); 3.22-3.30 (m, 2H), 3.40-3.51 (m, 2H), 3.78-3.88 (m, 2H), 3.94-4.00 (m, 5H), 4.31 (t, 2H), 6.11 (s, 2H), 6.80 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H); Mass Spectrum: M+H+ 562.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:26][CH2:25][C:22]2[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=2)=[O:17])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Reactant: Cc1ncc(CN)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 5-bromo-4′-methylbiphenyl-3-carboxylic acid (1.00 g, 2.75 mmol), (2-methylpyrimidin-5-yl)methanamine (0.406 g, 3.30 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumh (2.40 g, 6.32 mmol), N,N-diisopropylethylamine (1.91 mL, 11.0 mmol) and N,N-dimethylformamide (10 mL, 100 mmol) and the reaction stirred for 3 hours. The reaction was then quenched with water and extracted with ethyl acetate and washed with brine. The solvents were removed under reduced pressure and the residue purified by flash chromatography followed by prep HPLC to get the product as light yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9](F)[C:8]=2[F:16])[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:2][CH3:1])[C:8]=2[F:16])[CH2:6][CH2:5]1
Reactant: C[O-]
Reactant: O=Cc1ccc(C2CC2)c(F)c1F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C=O)ccc(C2CC2)c1F
Reaction time: 15 h
Yield: 91.6 %

Procedure:
Sodium methoxide (28% methanol solution, 3.43 g) was added at room temperature to a methanol (100 mL) solution of 4-cyclopropyl-2,3-difluorobenzaldehyde (2.16 g), and the mixture was stirred at 70 C for 15 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.11 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([NH2:18])([CH3:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.ClCCl>CO>[CH3:1][O:2][C:3]([C:4]1([CH3:17])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:7]=2[CH:24]([C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([OH:20])[CH:22]=2)[NH:18]1)=[O:19]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccc(OC)cc12
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Temperature: 25 °C
Yield: 15 %

Procedure:
To a solution of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (5.178 g, 19.5 mmol) and 3-hydroxybenzaldehyde (2.85 g, 23.4 mmol, 1.2 equiv.) in dry dichloromethane (80 ml) trifluoroacetic acid (1.5 ml, 19.5 mol, 1 equiv.) is added and the mixture is stirred under argon at room temperature. When TLC indicates the disappearance of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (1 day), a little methanol is added to dissolve the product precipitated during the reaction. The mixture is then diluted with dichloromethane (750 ml) and is washed with 2 M aqueous HCl, aqueous NaHCO3 and water, is dried and concentrated. Column chromatography (dichloromethane-ethyl acetate 9:17:1) of the residue gives 5.22 g (73%) of (1RS,3SR)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 183-184° C. from ethyl acetate-light petroleum) and 1.07 g (15%) of (1RS,3RS)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 175-177° C. from ethyl acetate-light petroleum).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:30])[C:14]1[CH:19]=[C:18]([S:20]([CH:23]2[CH2:25][CH2:24]2)(=[O:22])=[O:21])[N:17]=[C:16]([NH:26][CH:27]2[CH2:29][CH2:28]2)[CH:15]=1)(C)(C)C>ClCCl>[CH:27]1([NH:26][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([S:20]([CH:23]3[CH2:24][CH2:25]3)(=[O:22])=[O:21])[N:17]=2)[C:13]([OH:30])=[O:12])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1cc(NC2CC2)nc(S(=O)(=O)C2CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(NC2CC2)nc(S(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add trifluoroacetic acid (2 mL) to a solution of 2-cyclopropylamino-6-cyclopropanesulfonyl-isonicotinic acid tert-butyl ester (0.120 g, 0.355 mmol) in dichloromethane (2 mL) at 0° C. Stir the solution at room temperature for 3 h, concentrate and dry the title compound (0.076 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.500 g, 0.0014 mol) in dimethoxyethane (15 mL) and water (30 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.631 g, 0.00155 mol), sodium carbonate (0.374 g, 0.0035 mol) and tetrakis(triphenylphosphine)palladium (0) (0.163 g, 0.00014 mol) at 80° C. for 18 hours. The solid was filtered and washed with water. The solid was slurried in ethyl acetate for 18 hours and filtered, washing with ethyl acetate. The solid was dried in vacuo to give crude 4-[4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)-carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.523 g, 0.0010 mol) as a brown solid:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:6]2[O:7][C:13](=[O:14])[NH:9][N:8]=2)=[CH:10][CH:11]=1
Reactant: Cc1nc(Cl)ccc1C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)ccc1-c1n[nH]c(=O)o1
Temperature: 25 °C

Procedure:
6-Chloro-2-methylnicotinohydrazide (60 mg, 0.32 mmol) and 1,1′-carbonylbis(1H-imidazole) (58 mg, 0.36 mmol) were taken up in dimethylformamide (1.6 ml). The reaction was heated overnight to 60° C. It was then allowed to cool to room temperature, taken up in ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound.