Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:21])[N:9]([CH2:11][C@@H:12]3[CH2:14][C@H:13]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[N:7]3[C:8](=[O:21])[N:9]([CH2:11][C@@H:12]4[CH2:14][C@H:13]4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: O=c1n(C[C@@H]2C[C@H]2c2ccccn2)nc2cccc(Br)n12
Product: O=c1n(C[C@@H]2C[C@H]2c2ccccn2)nc2cccc(N3CCOCC3)n12
Temperature: 120 °C
Yield: 62.3 %

Procedure:
In a 1 mL microwave vial were placed 13-5 (22 mg, 0.064 mmol) and morpholine (1.00 g, 1.00 mL, 11.5 mmol). The vial was sealed and heated at 120° C. under microwave irradiation for 10 min. The reaction mixture was directly purified by reversed phase chromatography to give 14.0 mg (62%) of 13-6. 1H NMR δ (500 MHz, DMSO-d6): δ 8.44 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.01 (dd, J=9.3, 7.0 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 5.75 (d, J=7.0 Hz, 1H), 3.90 (dd, J=6.9, 3.9 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.12-3.03 (m, 4H), 2.25 (dt, J=8.5, 4.6 Hz, 1H), 1.84 (s, 1H), 1.23-1.15 (m, 2H). HRMS (ES) 352.1761 (M+H) found, 352.1768 required.
Reaction SMILES: [BH4-].[Li+].[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][C:6]=1[CH3:15])#[N:4]>C1COCC1.O>[OH:10][CH2:9][C:8]1[CH:13]=[CH:14][C:5]([C:3]#[N:4])=[C:6]([CH3:15])[CH:7]=1
Reactant: COC(=O)c1ccc(C#N)c(C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
Lithium borohydride (33 mg, 1.54 mmol) was added into a solution of methyl 4-cyano-3-methylbenzoate (245 mg, 1.40 mmol) in THF (3 mL) and the resulting mixture was stirred at RT for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (4×20 mL). The combined organic fractions were dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound as a colorless gum (195 mg, 95%). 1H NMR (CDCl3, 400 MHz) δ 7.58 (1H, d, J=7.9 Hz), 7.33 (1H, s), 7.26 (1H, m), 4.74 (2H, s), 2.55 (3H, s), 1.95 (1H, s). LC/MS (Method A): 144 (M+H)+. HPLC (Method F) Rt 3.95 min (Purity: 95.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)O.P(Br)(Br)[Br:16]>>[Br:16][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:14]
Reactant: BrP(Br)Br
Reactant: COC(=O)C(O)c1cccc(OC)c1
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
Methyl-m-methoxymandelate is reacted with phosphorous tribromide by the method of I. P. Beletskaya, Zh. Obshch. Khim., 34, 321 (1964) to give methyl bromo-(m-methoxyphenyl)acetate as a pale yellow liquid, and used below (without further purification).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56](Br)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(=O)([O-])[O-].[K+].[K+].C(COC)OC.C(OCC)(=O)C.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>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C:26]3[S:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[CH:6]=[O:5])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)=[CH:28][CH:27]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)cc2)[nH]1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C=O)[nH]5)cc4)s3)cc2[nH]1
Temperature: 110 °C
Yield: 66.2 %

Procedure:
A mixture of 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh3)4 (0.012 g) in 2.0M potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at 110° C. for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.085 g) as a bis-TFA salt: LCMS-ESI+: calc'd for C38H45N6O4S: 681.86 (M+H+); Found: 681.0 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([N:28](C)[C:29](=O)OC(C)(C)C)[CH2:24]4)=[N:21][CH:22]=2)=[CH:13][C:12]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[ClH:53]>C1COCC1>[ClH:43].[ClH:53].[ClH:43].[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:22]=[N:21][C:20]([N:23]4[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24]4)=[CH:19][CH:18]=2)=[CH:13][C:12]([C:37]2[CH:38]=[C:39]([Cl:45])[C:40]([OH:44])=[C:41]([Cl:43])[CH:42]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 65 °C
Yield: 40.1 %

Procedure:
To a solution of tert-butyl (1-(5-((3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (90 mg, 0.14 mmol) in THF (3 mL) was added TFA (2 mL). The reaction mixture was heated at 65° C. for 16 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (12.3 mg, 13%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.37 (s, 1H), 8.31-8.19 (m, 3H), 8.05 (d, J=8.8 Hz, 1H), 7.87 (dd, J=9.3, 2.7 Hz, 1H), 7.44 (s, 2H), 7.05 (d, J=9.3 Hz, 1H), 4.12-4.01 (m, 2H), 3.93-3.81 (m, 2H), 3.80-3.71 (m, 1H), 2.88-2.79 (m, 1H), 2.83 (s, 3H), 2.69-2.58 (m, 1H), 2.43-2.32 (m, 1H), 1.26-1.18 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 95.9% (AUC), tR=10.31 min.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].C([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1)=O.C(=O)([O-])O.[Na+]>O>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:1][NH2:2])=[CH:8][C:9]=1[OH:16])([OH:13])=[O:12]
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc(C(=O)O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NCc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (32 mg; 0.5 mmol) was added to a mixture of PAMAM 4.0 (EDA) (69 mg; 0.01 mmol), 4-formyl-2-hydroxybenzoic acid (83 mg; 0.5 mmol), and sodium hydrogen carbonate (42 mg; 0.5 mmol) in water (4 ml). The inhomogeneous orange mixture was stirred for four hours at room temperature, during which time it became homogeneous. The orange solution was then concentrated and the residue purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with ca. 32 4-carboxy-3-hydroxybenzylamine groups (91 mg). 1H and 13C nmr (D2O) shows mostly mono alkylation but with some signs of dialkylation of the terminal amino groups, both spectra show broad peaks. 13C nmr (D2O): δ37.0; 41.1; 50.9; 53.4; 55.5; 55.8; 61.5; 120.9; 122.2; 122.4; 132.3; 132.7; 135.0; 135.8; 163.5; 163.7; 169.0; 178.6; 179.3. 1H nmr (D2O): δ2.20; 2.35; 2.60; 3.15; 3.30; 3.55; 4.25; 6.68; 7.12; 7.55.
Reaction SMILES: S([O-])([O-])(=O)=O.[Zr+4:6].S([O-])([O-])(=O)=O.[P:12]([O-:16])([OH:15])([OH:14])=[O:13].[NH4+].[Zr].[P].[OH-].[Na+]>>[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[Zr+4:6].[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[P:12]([O-:16])([O-:15])([O-:14])=[O:13].[Zr+4:6].[Zr+4:6]
Reactant: O=P([O-])(O)O
Agent: [Zr+4]
Agent: [Zr]
Agent: O=S(=O)([O-])[O-]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
An aqueous zirconium sulfate solution and an aqueous ammonium dihydrogenphosphate solution were mixed at a ratio of zirconium and phosphorus of 2:3 to produce a precipitate. Then, pH of the resulting slurry was adjusted to 2 with an aqueous sodium hydroxide solution, followed by heating at 150° C. for 24 hours in the hydrothermal state to obtain crystalline zirconium phosphate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18]([O:24][CH2:23][CH2:22][NH:21][CH2:25][CH2:26][OH:27])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(Cl)c2ccccc2n1
Reactant: OCCNCCO
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(OCCNCCO)c2ccccc2n1
Temperature: 100 °C

Procedure:
A suspension of 4 g of 2-(1-methyl-5-nitro-2-imidazolyl)-4-chloroquinazolin and 1.6 g of diethanolamine in 25 ml of dimethyl formamide is heated at 100° C for 11/2 hours. After cooling, the resulting crystals are filtered off, washed with tetrahydrofuran and water, and dried to obtain the heading compound, m.p. 236°-239° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.CN.C[CH2:32][N:33](C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:33][CH3:32])[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CO
Solvent: CS(C)=O
Product: CNc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Methylamine (2M in THF, 0.129 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 4 h under microwave irradiation. Further methylamine (2M in THF, 0.129 ml, 0.26 mmol) was added and the mixture was again heated at 160° C. for 1 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method B). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (4.4 mg) as a pale yellow gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[CH2:23])[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nc(NCc3ccccc3OC)ccc2c1

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 2, step A, 500 mg, 1.46 mmol) was dissolved in 20 mL toluene. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Vinyltributyltin (462 mg, 1.46 mmol) and tetrakis(triphenylphosphin)palladium(0) (34 mg, 0.029 mmol) were added. The reaction mixture was refluxed overnight and evaporated. The residue was poured into 50 mL acetonitrile and extracted three times with heptane (50 mL each) to remove the tin products. The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine was obtained as a yellow oil (478 mg), MS: m/e=291.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C
Yield: 61 %

Procedure:
To a stirred solution of tert-butyl 4-((5-chloro-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (4 g, 9.09 mmol) in acetonitrile (50 mL), cesium carbonate (5.9 g, 18.09 mmol) and methyl iodide (6.95 g, 48.94 mmol) were added; resulting reaction mass was heated at 80° C. for 12 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (2.2 g, 53%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1.O1CCCC1.[OH-].[Li+]>CO>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NC=CC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
Isomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propenoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and tetrahydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, 8.4 mmol). The mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acidified to pH=4 with 1.0M aqueous hydrochloric acid. A brown precipitate formed. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoic acid, Isomer 1 (0.220 g, 78%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H), 7.27 (d, J=7.2 Hz, 2H), 7.03-6.88 (m, 1H), 6.60-6.42 (m, 2H), 4.33 (t, J=6.3 Hz, 1H), 3.64 (s, 2H), 2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51-1.22 (m, 2H), 0.90 (t, J=7.0 Hz, 3H). MS (M+1): 475.2.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.OC(C(F)(F)F)=O.[CH3:31][C:32]1[N:37]=[C:36]([CH2:38][C:39](O)=[O:40])[CH:35]=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:39](=[O:40])[CH2:38][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[N:37]=1
Reactant: Cn1cc(-c2ccc3c(c2Cl)CCN3)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3c2ccc(-c2cn(C)c4ncnc(N)c24)c3Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of 5-(4-chloro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (300 mg, 0.805 mmol), (6-methyl-2-pyridinyl)acetic acid TFA salt (213 mg, 0.805 mmol), HATU (306 mg, 0.805 mmol), in N,N-Dimethylformamide (DMF) (50 mL) under nitrogen at 0° C. was added DIEA (0.562 mL, 3.22 mmol). The reaction was stirred overnight at room temperature, then poured into water and stirred for one hour. A brown precipitate formed which was collected by filtration and washed with water. The solid was dissolved in ca. 25 mL chloroform, and purified by flash chromatography (0-100% EtOAc in chloroform→0-10% MeOH in EtOAc, 24-g column) to afford 5-{4-chloro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (144 mg) as a yellow solid. LC-MS (ES) m/z=433 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 3.24 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 4.00 (s, 2H), 4.35 (t, J=8.46 Hz, 2H), 5.69-6.08 (m, 2H), 7.16 (t, J=6.82 Hz, 2H), 7.20-7.25 (m, 2H), 7.66 (t, J=7.58 Hz, 1H), 8.03 (d, J=8.34 Hz, 1H), 8.13 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)=[C:24]([Cl:39])[CH:23]=2)([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.C(O)(=O)C.[OH-].[Na+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][CH:35]=3)=[C:24]([Cl:39])[CH:23]=2)([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: CC(C)(c1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1)c1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(c1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1)c1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To avoid reductive dehalogenation, the 2,2-bis[3,5-dichloro-4-(4-nitrophenoxy)phenyl]propane was reduced chemically, rather than catalytically hydrogenated. To a magnetically stirred slurry in a 1-liter Erlenmeyer flask of 53.5 g (0.088 mole) of the dinitro compound and 265 mL of acetic acid warmed to 50°-60° C. there was added a solution of 131 g of (0.58 mole) stannous chloride dihydrate in 132 mL of conc. hydrochloric acid over a 10-minute period. The exothermic reduction raised the temperature to about 100° C., and external heating was stopped. After stirring 1 hr, a chilled solution of 14.0 g (0.35 mole) of sodium hydroxide in 440 mL of water containing 1.0 g of ascorbic acid (antioxidant) was added. Thereafter, every few minutes, 2 g portions of sodium hydroxide were added until an alkaline reaction with pH paper was obtained. The insoluble product, 2,2-bis[3,5-dichloro-4-(4-aminophenoxy)phenyl]propane, was isolated as a white powder by filtration, washing with water containing 0.5 wt % of ascorbic acid, and drying to a constant weight in vacuo at 60° C. Yield, 42.0 g (87%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])#[CH:13]>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]#[C:13][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1F
Product: Cc1cc2ncc(C#Cc3ccccc3F)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-2-fluoro-benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.Cl[CH2:10][CH:11]=O>CCO>[N:1]1[CH:10]=[CH:11][N:3]2[C:4]([NH2:8])=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1cccc(N)n1
Reactant: O=CCCl
Solvent: CCO
Product: Nc1cccc2nccn12
Temperature: 75 °C
Yield: 80 %

Procedure:
2,6-diaminopyridine (5.0 g, 46 mmol) and chloroacetaldehyde (50% wt. soln in water, 6.4 mL, 50 mmol) were dissolved in absolute EtOH (120 mL). The solution was heated at 75° C. for 1 hour. The mixture was cooled and concentrated via rotavap. The residue was taken up in saturated NaHCO3 and EtOAc. The solution was extracted with EtOAc (3 times), dried over magnesium sulfate, and concentrated to give a brown solid. 4.85 g isolated (80% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1.CO>O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:22]1([CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH2:21]1)[CH2:1][C:2]2=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl may be added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.