Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:38][CH3:39]>ClCCl.N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:38][CH3:39])[CH:17]=3)[C:29]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (35 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more 4-(trifluoromethyl)-1-benzenecarbonyl chloride (18 mg, 0.086 mmol) was added. 2 hours later, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide (85 mg, 95%). 1H NMR (CDCl3) δ 2.10 (m, 2H), 2.37-2.59 (m, 7H), 3.15 (m, 2H), 4.02 (s, 3H), 4.83 (m, 1H), 5.68 (s, 2H), 7.34 (m, 2H), 7.80 (d, J=8.21 Hz, 2H), 8.04 (d, J=8.10 Hz, 2H), 8.38 (s, 1H), 8.67 (m, 2H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=526.3, Rt=1.93 min.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=3)[CH:8]=[CH:9][C:2]=12.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][F:26]>CN(C=O)C>[F:26][CH2:25][CH2:24][O:16][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:2]3[C:3]([CH:6]=2)=[N:4][O:5][N:1]=3)[CH:15]=[CH:14][CH:13]=1
Reactant: FCCBr
Reactant: Oc1cccc(-c2ccc3nonc3c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FCCOc1cccc(-c2ccc3nonc3c2)c1

Procedure:
600 mg (2.83 mmol) 3-benzo[1,2,5]oxadiazol-5-yl-phenol are dissolved in 15 mL DMF and stirred for 20 hours at room temperature in the presence of 1.15 g (1.25 eq.) cesium carbonate and 0.264 mL 1-bromo-2-fluoroethane. The reaction mixture is extracted with water and ethyl acetate, the combined organic phases are washed with water and brine, dried with magnesium sulfate and evaporated to dryness. The residue is column chromatographed (gradient from hexane to hexane/ethyl acetate 3:2) to yield the desired product as a pale yellow powder. MS(ES+): 259 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:74][C:73]3[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=3)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3ccc(F)cc3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15.8 mg, 48%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:15][C:14]=2[CH3:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:26]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][O:21][CH3:26])[CH:16]=[CH:15][C:14]=2[CH3:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(CCO)cc1CN(C(=O)OC(C)(C)C)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(C)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl cyclopropyl[5-(2-hydroxyethyl)-2-methylbenzyl]carbamate from the previous step (1 eq.) in THF (0.2 M) was added sodium hydride (2 eq.). The resulting suspension was stirred at RT for 30 min and then added iodomethane (8 eq.). After 12 h of heating at reflux, the reaction mixture was cooled to RT and quenched with sat. aq. NH4Cl. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a colorless oil. Further purification by way of column chromatography (SiO2, Hex→7:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.Cl[CH:16](OCC)[CH2:17]CCl.ClCCl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:14][CH:16]=[CH:17][N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(Cl)CCCl
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: ClCCCOc1ccc(-c2nccs2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
A solution of 4-(3-chloropropoxy)benzenecarbothioamide ax71 (0.3 g, 1 eq, 1.31 mmol) in ethyl alcohol (5 ml) is treated with 1,3-dichloro-1-ethoxy-propane (0.4 ml, 2.7 eq, 3.6 mmol) and the mixture is stirred at 110° C. during 4 h. The mixture is then poured into dichloromethane (10 ml) and is washed with water. The organic phase is dried over magnesium sulfate and concentrated. Purification by chromatography over silicagel (eluent: dichloromethane) affords 120 mg of 2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole i88.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9].Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: COc1ccc(C)c(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(O)cc1C=O
Temperature: 170 °C
Yield: 47.2 %

Procedure:
A stirred mixture of 5-methoxy-2-methylbenzaldehyde (24.9 g) and pyridine hydrochloride (100 g) is heated at 170° C. for 7 hours. Water (250 mL) is added cautiously to the reaction mixture at 140° C. and the very dark mixture is extracted twice with chloroform (250 mL), filtration through hyflo removes a small amount of insoluble black solid and aids separation. The organic phase is washed with 1 N hydrochloric acid (250 mL), with water (250 mL), with brine (250 mL), dried over magnesium sulphate and evaporated. The residue is washed with pentane to give 5-hydroxy-2-methylbenzaldehyde (10.66 g) as a cream solid, m.p. 116-118° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[N:14]([CH2:22][O:23][CH3:24])[C:13]=3[CH:25]=2)=[CH2:8])[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[N:14]([CH2:22][O:23][CH3:24])[C:13]=3[CH:25]=2)[CH3:8])[CH:2]=1
Reactant: C=C(c1cccnc1)c1ccc2c(c1)N(COC)c1nccnc1S2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCN1c2cc(C(C)c3cccnc3)ccc2Sc2nccnc21
Yield: 45.8 %

Procedure:
0.23 g of 8-[1-(pyridin-3-yl)vinyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 10 ml of ethanol and then hydrogenated in the presence of 0.056 g of 10% palladium-carbon (moisture content: 50%) in a hydrogen gas stream at room temperature for 26 hours. Thus 0.106 g of the title compound was obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc2oc(-c3ccc(N4CCCCC4)cc3)nc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture containing 2.48 g (10 mmoles) of 5-chloro-2-(4-fluorophenyl)benzoxazole, 2.55 g (30 mmoles) of piperidine and 15 ml of NMP is heated with stirring under nitrogen atmosphere at 100° C. for 16 hours. The reaction is complete as judged by GC analysis. The mixture is cooled, poured into 100 ml of water and stirred for 30 minutes. The title compound (3.05 g, 97 percent yield) is filtered and washed. It has a melting point of 162° C.-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(C)c3)C2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)O)cc3Cl)C2)c1
Yield: 53.8 %

Procedure:
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (820 mg) and 1N NaOH solution (4.1 ml) in MeOH (20 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and brine. The aquous solution was adjusted to PH 5.4 with 5% HCl solution and extracted with THF and AcOEt. The solvent was evaporated in vacuo and The precipitate was washed with n-hexane to give (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCCOc1ccccc1)c1cc(O)ccc1O
Reaction time: 12 h

Procedure:
A solution of 4-(2,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
Potassium carbonate (350 mg, 2.53 mmol) was added to a solution of compound 2 (210 mg, 0.84 mmol) in 4 mL of anhydrous DMF at 0° C. After stirring of reaction mixture for 20 min, a solution of tert-butyl (3-bromopropyl)carbamate (200 mg, 0.84 mmol) in anhydrous DMF (3 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford compound 21a (78.8%, 270 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][O:14][C:15](=[O:38])[CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:13][O:14][C:15](=[O:38])[CH2:16][CH:17]1[CH2:18][CH2:19][CH:20]([C:23]2[CH:24]=[CH:25][C:26]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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
Product: COC(=O)CC1CCC(c2ccc(-c3ncc([N+](=O)[O-])cc3OC)cc2)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-methoxy-5-nitro-pyridine (0.10 g, 0.53 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.2 g, 0.56 mmol, 1.05 equiv) in 5 Ml DME was added 0.5 Ml saturated potassium carbonate solution and 10 mg Pd(PPh3)4 catalyst. The reaction was heated to 100° C. for 2 h. The crude reaction mixture was then concentrated in vacuo and then loaded directly onto a silica gel column. Elution with 30% EtOAc/hexanes afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.19 (m, 2H) 1.15 (d, J=13.14 Hz, 1H) 1.46-1.59 (m, 1H) 1.51 (dd, J=112.38, 2.78 Hz, 2H) 1.81 (d, J=5.56 Hz, 4H) 2.26 (d, J=6.82 Hz, 2H) 3.61 (s, 3H) 4.00 (s, 3H) 7.36 (d, J=8.34 Hz, 2H) 7.90 (d, J=8.34 Hz, 2H) 8.20 (d, J=2.02 Hz, 1H) 9.05 (s, 1H); (M+H)+385.1.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][N:67]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
The solution of N,N-dimethylglycine (100 mg, 0.24 mmol) in DCM (1 mL) was treated with N,N-diisopropylethylamine (83 uL, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol) and 1-hydroxybenzotriazole (38.8 mg, 0.29 mmol) followed by 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol). The mixture was stirred at rt overnight then purified by HPLC. 20 mg (17%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.91 (s, 1H), 7.47-7.35 (m, 5H), 6.88 (s, 1H), 6.82 (d, 1H), 6.75 (d, 1H), 6.50 (s, 1H), 5.49 (s, 2H), 5.13 (s, 2H), 4.66 (d, 1H), 4.23 (d, 1H), 3.48 (m, 1H), 3.25-3.15 (m, 2H), 3.12-3.04 (m, 1H), 2.76 (td, 1H), 2.29 (s, 6H), 2.17 (s, 2H), 1.72-1.61 (m, 2H); LC-MS m/z [M+H]+ 503.3, RT 2.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2[C:27](C3N=CN(C4C=CC=CC=4)C=3)=[C:26](C(F)(F)F)[O:25]N=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:26](=[O:25])[CH3:27])=[C:11]([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)no1
Product: CC(=O)c1c(-c2ccc(Cl)cc2)noc1C(F)(F)F
Yield: 60 %

Procedure:
As described for Example 1e, 3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazole (36 g, 145.4 mmol), instead of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, was converted to the title compound (25.2 g, 60%) which was obtained as a light orange oil. MS: m/e=287.9 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.O[C:12]([C:15](O)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cccc(Br)c2)OC1(C)C
Yield: 77 %

Procedure:
The title compound (77%, oil) was prepared from 3-bromophenylboronic acid and pinacol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:22])=[CH:6][CH:5]=1.[H-].[Na+].[CH:26](Br)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]=2[CH3:22])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CCCc2c(C)[nH]c3ccccc23)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCCc2c(C)n(C(c3ccccc3)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step 2 (1.66 g, 4.86 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) under N2 atmosphere. The mixture was stirred for 1 h at room temperature, followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirred overnight at room temperature. Water (500 mL) was added to reaction mixture, it was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to a brown syrup, which was purified by silica-gel chromatography using 10% EtOAc/hexanes as eluent to isolate 4-[3-(1-Benzhydryl-2-methyl-1H-indol-3-yl)-propyl]-benzoic acid methyl ester as a white solid in 76% (1.47 g) yield.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.Cl>CC(C)=O.CN(C)C=O>[O:23]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:18][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: BrCC1CCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Nc1nc(N)c2c(ccc3c2ccn3CC2CCCO2)n1
Reaction time: 24 h

Procedure:
In a manner similar to that of Example 2, 3.98 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in ca. 260 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 3.63 g. tetrahydrofurfuryl bromide. After stirring the mixture at ca. 25° for 24 hours, 0.21 g. ca. 50% sodium hydride-mineral oil dispersion are added. Stirring is continued for one-hour, 0.73 g. tetrahydrofurfuryl bromide is added, and, after stirring for 6 hours, the reaction mixture is kept at ca. 25° for ca. 70 hours. Processing of the reaction mixture in the manner described in Example 2 (Method A) yields a brown gum which is dissolved in 40 ml. N hydrochloric acid. Dilution of the aqueous acidic solution with 40 ml. acetone gives crystals that are collected and twice recrystallized from methanol-acetone to yield 1.20 g. title compound as a monohydrochloride salt bearing one-third molecule of water per molecule of diamine salt, m.p. 310°-311° (dec.).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[S:13][CH:14]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.S(Br)([Br:21])=O>>[Br:21][C:14]1[S:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: O=S(Br)Br
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)cs1
Product: COC(=O)c1cc(-c2cnc3cccnn23)c(Br)s1
Temperature: 50 °C

Procedure:
Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (690 mg, 2.66 mmol) was dissolved in thionyl bromide (5 mL, 64.5 mmol) and heated at 50° C. in a sealed tube for 4 h. The solution poured over ice and quenched with ammonium hydroxide. The aqueous layer was extracted with dichloromethane (×3). The organic layers put together, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as a light brown solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.66 (d, 1H); 8.27 (s, 1H); 8.25 (s, 1H); 8.25 (d, 1H); 7.35 (dd, 1H); 3.85 (s, 3H). LRMS (APCI) calc'd for (C12H8BrN3O2S) [M+H]+, 338.0. found 337.9.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC1(C)CCCNC1
Product: CC1(C)CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 3,3-dimethylpiperidine (1.2 equiv) to give 164 (12.1 mg, M+1 409.1)