Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]#[N:17])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][N:3]12.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:27][OH:28]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[N:27][OH:28])[NH2:17])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][N:3]12
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Yield: 93.7 %

Procedure:
64.7 g (258 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were heated to reflux for 2.5 hours with 52.8 g (497 mmol) of sodium carbonate and 42.36 g (608 mmol) of hydroxylamine hydrochloride in 1.5 l of alcohol and 300 ml of water. The alcohol was evaporated and the suspension obtained was cooled to 0°. The crystals were filtered off under suction, washed with water and dried. There were obtained 68.5 g (93%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of decomposition point 216°.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([Br:22])=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)(C)(C)C.IC.[H-].[Na+]>CN(C=O)C>[Br:22][C:19]1[N:17]2[N:18]=[C:13]([N:10]3[CH2:11][CH2:12][C@H:8]([NH:7][CH3:6])[CH2:9]3)[CH:14]=[CH:15][C:16]2=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 103.6 %

Procedure:
[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.2 g, 3.1 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (342 uL, 5.42 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (251 mg, 6.2 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 951 mg crude product carried on as is to part B. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:19])[CH2:6]1)C.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]([NH2:32])=[NH:31])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:6][C:7](=[O:19])[NH:8][C:9]4[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:10]=4[C:11]=3[N:31]=2)=[CH:21]1
Reactant: Cc1cc2c(cc1C)C(=O)C(=CN(C)C)CC(=O)N2
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Product: Cc1cc2c(cc1C)-c1nc(Cc3c[nH]c4ccccc34)ncc1CC(=O)N2
Yield: 72 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 72%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28]C)=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>CCOCC>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([OH:28])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
174 mg (0.376 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 3 were mixed with 30.0 mg (0.751 mmol) of sodium hydroxide, 32 ml of water and 3 ml of ether and the mixture was stirred at room temperature for 24 hours. After concentrated under reduced pressure, the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated under reduced pressure to obtain 134 mg of 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[F:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:48](=[O:49])[C:47]3[CH:46]=[CH:45][C:44]([CH2:43][N:40]4[CH2:39][CH2:38][CH:37]([F:36])[CH2:42][CH2:41]4)=[CH:53][CH:52]=3)[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(CN2CCC(F)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCC(F)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.65 ml, 0.65 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl) ethyl]pyrazole-1-carboxylate (150 mg, 0.43 mmol, 1 eq) and methyl 4-[(4-fluoropiperidin-1-yl)methyl]benzoate (131 mg, 0.52 mmol, 1.2 eq) in THF (0.5 ml). The reaction mixture was stirred at ambient temperature for 1 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 39-49% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (33 mg, 16% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[O:31])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1cccc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](Cn2ccccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (370 mg) in DMF (8.0 mL) were added 2(1H)-pyridinone (87 mg) and potassium carbonate (158 mg), and the mixture was heated at 80° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (44 mg).
Reaction SMILES: CC(C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6]C)=[O:5].FC1[CH:34]=[C:35]([C:40]2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)[CH:36]=CC=1F.N[C@H](C(N)=O)CC(C)C>>[NH2:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])[CH2:34][CH:35]([CH3:40])[CH3:36]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Agent: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCN(C)C2)C(N)=O

Procedure:
Compound 49 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-leucine amide. 1H NMR (CDCl3) δ 7.49-7.58 (m, 2H), 7.34-7.38 (m, 1H), 7.18-7.24 (m, 1H), 4.50 (m, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 2.53 (s, 3H), 1.71-1.82 (m, 3H), 0.88-0.99 (m, 6H). LCMS (+ESI) m/z=406.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1.[C:19](Cl)(=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[Sn].C(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]2[C:5](=[CH:6][C:7]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]=3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(Cc2cc3ccccc3s2)c1
Agent: O=C=O
Agent: [Sn]
Solvent: ClCCl
Product: COc1ccc(-c2c3ccc(OC)cc3cc3sc4ccccc4c23)cc1
Yield: 62.7 %

Procedure:
To a cold (-78° C.) solution of 2-(3-methoxybenzyl)-benzo[b]thiophene (2.10 g, 8.26 mmol) and p-anisoyl chloride (1.48 g, 8.67 mmol) in anhydrous methylene chloride (31 mL) was added tin IV chloride (2.90 mL, 24.8 mmol, 3 eq) dropwise over a period of 24 minutes. After stirring overnight in the warming dry ice bath and at ambient temperature for 7 hours the reaction mixture was poured onto water (175 mL) and the organics were extracted with diethyl ether (2×300 mL). The extracts were combined, and washed with brine. Silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (97/3 petroleum ehter/ethyl acetate) to give the title compound as a white solid (1.92 g, 63%): mp 158-159° C.; MS (+FAB): [M+] 370; Anal. Calc. for C24H18O2S: C, 77.81, H, 4.90, N, 0.00. Found: C, 78.00, H, 4.76, N, 0.03.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18].Cl>O.CS(C)=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1)#[N:18]
Reactant: Nc1cncnc1
Reactant: N#Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of dimethyl sulfoxide was added 1.40 g (12.5 mmol) of potassium tert-butoxide, and to the solution was added 951 mg (10.0 mmol) of 5-aminopyrimidine while cooling with water. After stirring at room temperature for 1 hour, 0.54 ml (5.0 mmol) of 2-fluorobenzonitrile was added thereto while cooling with water, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and the mixture was adjusted to pH 7.0 with 1 N hydrochloric acid, and filtered. The filter residue was dissolved in 200 ml of acetone, and the acetone solution was filtered. The filtrate was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 0.53 g (2.70 mmol) of 5-[N-(2cyanophenyl)amino]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[C:6]([N+]([O-])=O)[CH:5]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:22])[S:21][C:6]=2[CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC)cc2s1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4-formyl-3-nitro-benzoic acid methyl ester (15.22 g, 72.78 mmol), mercapto-acetic acid ethyl ester (8.70 mL, 79.3 mmol) and K2CO3 (12.87 g, 93.12 mmol) in 140 mL of anhydrous DMF was heated at 50° C. overnight. After cooling to rt, the mixture was poured into 1 L of ice-water and the resulting mixture was stirred for 40 min. The solid formed was filtered and washed with 4×70 mL of water. After drying, benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester 6-methyl ester was obtained as a pale solid. 1H NMR (CDCl3, 200 MHz) δ 8.56 (s, 1H), 8.09-7.97 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.40 (t, J=6.8 Hz, 3H). MS (EI): cal'd 265.0 (MH+), exp 265.0 (MH+).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])[OH:4].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCO>C(Cl)Cl>[C:15]([NH:19][CH2:2][CH:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])[OH:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: N#Cc1cc(F)cc(C(O)CBr)c1F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)NCC(O)c1cc(F)cc(C#N)c1F

Procedure:
A stirred mixture of 10.2 g of 3-(2-bromo-1-hydroxyethyl)-2,5-difluorobenzonitrile, 100 mL of t-butylamine and 100 mL of EtOH is heated at reflux under N2 for 2 hours. The mixture is stripped in vacuo and the residue is partitioned between 50 mL of H2O and 100 mL of 10% NaOH and 3×100 mL of CH2Cl2. The CH2Cl2 layers are combined, washed with 2×50 mL of H2O, dried with Na2SO4 and evaporated in vacuo to afford 9.44 g of partly crystallized dark orange material. This material is dissolved in 100 mL of CH2Cl2 and extracted with 50 mL of 10% aqueous HCl, 50 mL of H2O, 50 mL of 10% HCl and 50 mL of H2O. The combined aqueous acidic extracts are basified with 10% aqueous NaOH in ice and extracted with 3×100 mL of CH2Cl2. The CH2Cl2 extracts are washed with 2×50 mL of H2O, dried with Na2SO4 and stripped in vacuo to give an off-white solid. Recrystallization from hexane gives 5.8 g of 3-[2-(tert-butylamino)-1-hydroxyethyl]-2,5-difluorobenzonitrile, m.p. 99°-101° C. The mass spectrum shows an M+1 ion at 255. Infrared and NMR spectral data are consistent.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C(C)(C)C)[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O1CCOCC1.C(OCC)(=O)C>[F:49][C:46]([F:47])([F:48])[C:38]1[CH:37]=[C:36]([CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=1)[CH2:35][N:22]([C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[NH:8][CH2:9][CH2:10][CH2:11]1)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=1
Reactant: CC(C)(C)OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (S)-9-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxy-ethyl)-2H-tetrazol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.140 mmol) in 4 M hydrochloric acid/dioxane (10 mL). After stirring overnight at room temperature, neutralize the reaction with aqueous sodium carbonate and dilute with ethyl acetate (20 mL). Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (10-40%) to provide the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].I[C:15]1[C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:13][O:12][C:8]1[CH:7]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])[C:24](=[O:25])[C:23]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=1[NH:6]2
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc2[nH]c3c(C(=O)O)cccc3c(=O)c2c(OC)c1OC

Procedure:
From 3,4,5-trimethoxyaniline (3.8 g) and 2-iodoisophthalic acid (5 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:5]=[C:6]([CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>CO>[CH3:1][NH:2][CH2:12][CH2:11][CH:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: CN
Reactant: CCC(Oc1ccccc1OC)c1cccc(Cl)c1
Solvent: CO
Product: CNCCC(Oc1ccccc1OC)c1ccccc1

Procedure:
A reaction mixture consisting of 200 ml. of methylamine, 225 ml. of methanol and 75 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene was heated in an autoclave for 12 hours at 140° C. The reaction mixture was cooled, and the solvent was removed by evaporation. The semisolid residue was mixed with concentrated aqueous sodium hydroxide. The reasulting mixture was extracted several times with ether. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine, formed in the above reaction, was insoluble in the alkaline solution and was extracted therefrom with ether. The ether extracts were combined, and the combined extracts washed with water and dried. The ether was removed therefrom in vacuo leaving the amine as a dark colored residue. The residue was dissolved in ether and 1 equivalent of oxalic acid in methanol added slowly. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate formed an insoluble precipitate which was collected by filtration, and the filter cake washed with ether and dried. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate melted at 150°-152° C. The NMR spectrum of the compound was consistent with the expected structure.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:21]1[CH2:22][CH2:23][CH:19]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20]1
Reactant: IC1CCOC1
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC2CCOC2)cc1
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a suspension of methyl 4-sulfanylbenzoate (0.85 g, 5.05 mmol), potassium carbonate (1.39 g, 10.1 mmol) in DMF (10 mL) at room temperature was added 3-iodotetrahydrofuran (1.00 g, 5.05 mmol). The resulting suspension was stirred for 16 hours. The reaction mixture was diluted with DCM (25 mL), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (25 mL) and washed with water (3×15 mL) and saturated aqueous brine solution (1×15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.03 g, 86%) as a yellow solid. ESI-MS m/z calc. 238.1. found 239.3 (M+1)+; Retention time: 1.47 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.91-7.83 (m, 2H), 7.48-7.39 (m, 2H), 4.16-4.08 (m, 2H), 3.91-3.72 (m, 5H), 3.55 (q, J=7.6 Hz, 1H), 2.49-2.35 (m, 1H), 1.86-1.74 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16](Cl)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].[C:24]1([O-:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>[Cu]Cl.COCCOCCOCCOCCOC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Cl)c2)cc1
Reactant: [O-]c1ccccc1
Agent: Cl[Cu]
Agent: COCCOCCOCCOCCOC
Agent: [Na+]
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
A mixture of 456.2 g (1.30 mol) of (4-ethoxyphenyl)-(dimethyl)-(3-(3-chloro-4-fluorophenyl)propyl)silane, 232.2 g (2.00 mol) of sodium phenolate, 13 g of copper(I) chloride and 500 ml of tetraglyme was heated to 240°-255° C. for 1.5 h. After cooling the reaction mixture to 90° C., a larger part of the solvent was removed by distillation at 90°-140° C. internal temperature and 0.4 Torr (about 400 g). The crude product was then stirred at room temperature with 500 ml of 2N sodium hydroxide solution and extracted twice using 800 ml of hexane each time. The organic extracts were washed five times with 300 ml of water each time, dried over sodium sulfate and evaporated. The crude product thus obtained (486.1 g/92%) was distilled over a 50 cm split tube column. 233 g (44%) of (4-ethoxyphenyl)-(dimethyl)-(3-(4-fluoro-3-phenoxyphenyl)propyl)silane were obtained as a colorless oil of b.p.0.04 =208°-212° C., the purity of which was determined to be 95.2% by gas chromatography.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[CH:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 50 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (101 mg, 0.17 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methanesulfonamide (147 mg, 0.44 mmol), sodium carbonate (45 mg, 0.43 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.2 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 89 mg (50% yield, 69% purity) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8]C2CCCCO2)=[C:6]([O:17][CH3:18])[CH:5]=1)[CH:2]=[CH2:3].C([Li])(CC)C.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C>C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([O:17][CH3:18])[C:7]([OH:8])=[C:15]([B:28]([OH:29])[OH:27])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CCc1ccc(OC2CCCCO2)c(OC)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=CCc1cc(OC)c(O)c(B(O)O)c1
Reaction time: 0.17 h
Yield: 41 %

Procedure:
2-(4-Allyl-2-methoxyphenoxy)tetrahydropyran (2.0 g, 8.05 mmol) was dissolved in dry THF (70 ml) and the solution cooled to −78° C. sec-Butyl lithium (1.3M in hexanes, 7.4 ml, 9.62 mmol) was added dropwise with stirring over 10 minutes, the reaction was stirred at −78° C. for 2 hours. Triisopropoxy borane (3.4 ml, 14.6 mmol) was added and stirring continued for 4hours at −78° C. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (2×200 ml). The combined extracts were dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane and the solid filtered off to give the title compound (41%); MS 207 (M-H)−; HPLC retention time (system 1) 2.73 minutes.