Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[OH:12][C:11]1[C:3]([NH:2][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Reactant: O=C(O)CCCCc1ccccc1
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCc1ccccc1)Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (50 mg, 0.256 mmol) and 5-phenylvaleric acid (54.8 mg, 0.307 mmol) were dissolved in N,N-dimethylformamide (1.3 mL), diethyl cyanophosphate (45.7 μL, 0.307 mmol) and triethylamine (120 μL, 0.896 mmol) were added, and the mixture was stirred at room temperature for 15 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (21.8 mg, yield 26%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[N:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1>>[ClH:1].[ClH:1].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[N:3]=2)[CH2:33][CH2:32]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3ccc(Cl)c(Cl)c3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
225 mg of the product obtained in Stage 1 above and 285 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 168 mg of expected product is recovered.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)CC(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:20][CH2:21][Cl:22])[C:6]=2[CH:5]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: ClCCCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40 ml of a sodium hydroxide solution (50% by weight) are added to a solution of 2.34 g (10 mmol) of 2-chlorophenothiazine, 4.73 g (30 mmol) of 1-bromo-3-chloropropane and 0.34 g (1 mmol) of tetrabutylammonium hydrogenosulfate in 40 ml of 4-methylpentan-2-one. The mixture is stirred at ambient temperature for 48 hours. After customary treatment of the organic phase, drying over sodium sulfate, evaporation of the solvent and purification by chromatography on silica gel, 2.17 g of pure product are obtained (eluant: petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[N:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[N:23]=[CH:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-trifluoromethyl-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7].[NH3:14]>C(OCC)(=O)C>[C:2]([NH:14][C:6](=[O:7])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])(=[S:1])[NH2:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Into 75 ml of dry ethyl acetate, were added 7.3 g of anhydrous potassium thiocyanate and 15.7 g of 2,2,2-trichloroethyl chloroformate. The mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was cooled in ice water, followed by an addition of an aqueous ammonia solution (29%) to render the reaction mixture alkaline. The solvent was removed under reduced pressure. The residue was treated with a water/methanol mixed solvent and the reaction product was obtained in a powdery form through filtration. It was then washed thoroughly with water to obtain 14.5 g of 2,2,2-trichloroethyl N-thiocarbamoylcarbamate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:52])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:49][CH2:50][CH3:51])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][C:36]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)=[C:35]([OH:48])[CH:34]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][O:11][C:12](=[O:52])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:49][CH2:50][CH3:51])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][C:36]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)=[C:35]([OH:48])[CH:34]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCN)CC2
Reaction time: 2 h
Yield: 110.1 %

Procedure:
2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(6-ethyl-4-(4-fluorophenyl)-3-hydroxyphenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate (55.4 mg, 0.07 mmol) was added to dichloromethane (4 mL), followed by anisole (30 mg, 0.28 mmol) and trifluoroacetic acid (4 mL). The solution was stirred for 2 hours, concentrated under reduced pressure, and purified on a short silica column (chloroform/methanol) to afford 48 mg of product. NMR (CDCl3): 0.90, t (3H); 1.14, t (3H), 1.50, m (2H); 1.62, m (2H); 1.87, m (2H); 2.27, m(3H); 2.54, q (2H); 2.58, m (4H); 3.42, b (2H); 4.14, m (6H); 4.44, b (1H); 6.47, d (1H); 6.57, s (1H); 6.80, m (2H); 6.95, s (1H); 7.10, dd (2H); 7.40, dd (2H); 8.81, b (3H). Mass Spec (EI): m/z=623.4 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[Si:23]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33](I)[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>C(OCC)(=O)C.CCCCCC.CN(C)C=O>[Si:23]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH:35]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[CH2:36]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(I)C1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Yield: 15.2 %

Procedure:
A solution of 3- (3-oxo-2, 3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (870 mg), 1- (tert-butyldimethylsilyl)oxy-3-iodocyclohexane (1.5 g), potassium tert-butoxide (472 mg) and 18-crown-6 (80 mg) in 15 N,N-dimethylformamide (10 ml) was stirred for 2 hours at room temperature. A reaction mixture was diluted with a mixture of ethyl acetate (150 ml) and n-hexane (50 ml), which was washed in turn with water (50 ml), 1N-aqueous sodium hydroxide solution (50 ml×3) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (80 ml) eluting in turn with 25%, 33% and 50% ethyl acetate in dichloromethane to give 3-[2-{3-(tert-butyldimethylsilyloxy)cyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1, 5-a]-pyridine (0.23 g).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:19][CH:20]=1
Reactant: OCCCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
tert-Butyldimethylchlorosilane (1.13 g) and imidazole (513 mg) were added to a solution of 4-(4-bromophenyl)butan-1-ol (1.15 g) in N,N-dimethylformamide (35 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→50:1→20:1) to give the title compound (1.78 g, quant.).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:13]([F:20])[C:12]=1[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:25][CH2:24]1>C(COC)OC.FC(F)(F)S(O)(=O)=O>[F:7][C:32]1[CH2:33][CH2:34][CH:29]([C@H:26]2[CH2:27][CH2:28][C@H:23]([CH2:22][CH2:21][C:12]3[C:11]([F:10])=[CH:16][C:15]([CH2:17][CH2:18][CH3:19])=[CH:14][C:13]=3[F:20])[CH2:24][CH2:25]2)[CH2:30][CH:31]=1
Reactant: CCCc1cc(F)c(CC[C@H]2CC[C@H](C3CCC(=O)CC3)CC2)c(F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COCCOC
Product: CCCc1cc(F)c(CC[C@H]2CC[C@H](C3CC=C(F)CC3)CC2)c(F)c1

Procedure:
1.1 ml of diethylaminosulphur trifluoride (DAST) are added dropwise in 3 portions over 60 hours to a solution of 1.7 g of 4-{trans-4-[2-(2,6-difluoro-4-propylphenyl)ethyl]cyclohexyl}cyclohexanone in 30 ml of dimethoxyethane and 0.1 ml of trifluoro-methanesulphonic acid. The reaction solution is subsequently partitioned between sodium carbonate solution/ether. The organic phase is washed twice with water and the aqueous phases are individually extracted twice with ether. The organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated completely. The crude product obtained is chromatographed over silica gel and gives 1-fluoro-4-{trans-4-[2-(2,6-difluoro-4-propylphenyl)ethyl]cyclohexyl }cyclohex-1-ene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:20]([N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:24]=[N:23]1)[CH3:21]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1

Procedure:
The subtitled compound (0.64 g) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS[M+H-C4H8]+=289 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H), 7.35-7.23 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.68 (t, J=7.3 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 1.53 (t, J=7.3 Hz, 3H), 1.43 (s, 9H)
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.F[C:35](F)(F)C(O)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C.C[O-].[Na+].Cl>C(Cl)Cl>[C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(=[O:5])[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (81 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (3 mL), triethylamine (0.25 mL, 1.79 mmol), and acetic anhydride (0.085 mL, 0.90 mmol), and the resulting mixture was stirred at r.t. for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in MeOH (3.6 mL) and treated with NaOMe (3.6 mL, 1.79 mmol, 0.5 M in MeOH) for 1 h at r.t. 1 M HCl was added until pH was about 3-4, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 37 mg of the title compound as an off-white solid. MS: (+) m/z 395.38 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[CH2:11][C:12]([N:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[CH2:15][CH3:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[CH2:11][CH2:12][N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)C(=O)Cc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(CC)CCc2ccccc2OCc2ccccc2)cc1
Yield: 23 %

Procedure:
Ethyl 4-[N-(2-benzyloxybenzylcarbonyl)-N-ethylamino]benzoate (8.1 g) was dissolved in THF (20 ml) and 1M borane tetrahydrofuran complex added. The reaction mixture was heated at reflux for 1 hour and cooled. 2N Hydrochloric acid (20 ml) was added. The volume of the reaction mixture was reduced to half the original by evaporation. Water (100 ml) was added and made basic (pH 8) by the addition of solid potassium carbonate and the mixture extracted with diethyl ether (3×30 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was purified by MPLC, eluting with 1:1 dichloromethane/hexane, to give ethyl 4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate (1.8 g) m.p. 76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:24][C:25]=2[O:27][CH:28]([CH3:30])[CH3:29])[N:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][C:57]1=[O:62].[I-].[Na+]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34][N:59]3[CH2:60][CH2:61][N:56]([CH3:55])[C:57](=[O:62])[CH2:58]3)=[CH:24][C:25]=2[O:27][CH:28]([CH3:29])[CH3:30])[N:20]=[CH:19][N:18]=1
Reactant: CN1CCNCC1=O
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)cc(OC(C)C)c23)c2c1OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (0.320 g, as a 1:1.3 wt.:wt. mixture with triphenylphosphine) and 1-methylpiperazin-2-one (0.280 g) was dissolved in 2-methoxyethanol (7 ml), then sodium iodide (0.040 g) was added and the reaction mixture was then heated at 110° C. with stirring for 24 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (70 ml) and washed with water:brine (1:1) then water then brine and dried over magnesium sulfate before filtration and evaporation of solvents under reduced pressure. The residues so resulting were then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained 4-(3-{4-[5-chloro-7-(3-methoxy-prop-1-ynyl)-benzo[1,3]dioxol-4-ylamino]-5-isopropoxy-quinazolin-7-yloxy}-propoxy)-1-methyl-piperazin-2-one (0.086 g) as a white foam; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.02 (quin, 2H), 2.61 (t, 2H), 2.72 (t, 2H), 2.96 (s, 3H), 3.18 (s, 2H), 3.33 (t, 2H), 3.45 (s, 3H), 4.15 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.82 (d, 1H), 7.05 (s, 1H), 8.51 (s, 1H), 9.41 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[Cl-].[CH3:27][Zn+]>C1COCC1.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>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:4]2[N:3]=[C:2]([CH3:27])[N:7]3[C:8](=[O:11])[NH:9][N:10]=[C:6]3[C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12

Procedure:
To a stirred solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.128 mmol) and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in THF (0.5 mL) at room temperature under argon was added 2.0 M methylzinc chloride solution in THF (0.25 mL, 0.5 mmol). The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous NH4Cl. EtOAc (5 mL) and water (5 mL) were added and the layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with 40% EtOAc-hexanes to obtain 40 mg of the title compound as a white solid. HPLC/MS: retention time=3.883 min, [M+H]30 =371.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]1[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]1.CN(C)C=O.[Li][N:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>CCOCC>[C:32]1([N:24]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[C:25](=[O:26])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Reactant: [Li]N(C(=O)OC(C)(C)C)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 2 h

Procedure:
Pentane (350 mL) was added to tert-butyl phenylcarbamate (20.81 g, 107.7 mmol) to form a suspension. BuLi (67.3 mL, 107.7 mmol) in hexanes was added dropwise over 1 hour. During the addition a clear solution formed briefly then a white precipitate formed. After the addition was complete the mixture was stirred for 1 hour then the solid was collected on a glass frit, washed with pentane (2×20 mL), and dried under reduced pressure to afford LiN(Boc)Ph (16.6 g, 77.4%). 2-Bromomethylphenyl boronic acid pinacol ester (compound 9) (4.66 g, 15.7 mmol) and N,N-dimethylformamide (DMF) (35 mL) were combined to form a clear colorless solution. Then solid LiN(Boc)Ph (3.13 g, 15.7 mmol) was added in small portions over three minutes. The mixture was stirred for 2 hours then the white suspension was poured into water (250 mL). Et2O (150 mL) was added and the organics were separated, dried with brine then magnesium sulfate. Filtration followed by evaporation afforded the product as a white solid. 1H NMR (CDCl3, 250 MHz): 7.77 (d, 1H), 7.0-7.5 (m, 8H), 5.19 (s, 2H), 1.39 (s, 9H), 1.27 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([C:34]#[CH:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:35]#[C:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#Cc1cccc(F)c1
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 62.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with (3-fluorophenyl)-ethyne (241 mg, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-(3-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (247 mg, 64%). MS (ES+) m/z: 396 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH2:16][CH2:15]1)=[O:13].[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12](=[O:13])[CH2:11][S:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:15][CH2:16]1)(=[O:26])[CH3:24]
Reactant: O=C(CSc1nc2ccccc2s1)N1CCNc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CSc2nc3ccccc3s2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a 0° C. solution of compound 41 (0.41 g, 1.20 mmol) in dry CH2Cl2 (20 mL) were added Ac2O (1.12 mL, 12.0 mmol) followed by dropwise addition of Et3N (1.12 mL, 8.00 mmol), and DMAP (10 mg) The reaction was stirred for 18 h under N2 at room temperature. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (CH2Cl2/EtOAc 1:1), and triturated from CH2Cl2/hexanes to afford 48 as a yellow solid (0.24 g, 52%); MS m/z: 384 (M+H)+. Anal. Calcd. For, C19H17N3O2S2.0.1H2O: C, 59.23; H, 4.92; N, 10.91; S, 16.64. Found: C, 58.84; H, 4.55; N, 10.55; S, 16.32.