Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>ClCCl.CS(C)=O.[Cl-].[Na+].O>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH:21]=[O:22]
Reactant: O=C(CCCCO)NC1Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCCCC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C

Procedure:
A solution of 1.11 mL (12.8 mmol) oxalyl chloride in 35 mL of dichloromethane is cooled to −80° C. under argon atmosphere. 2.33 mL (32.7 mmol) of dimethylsulfoxide in 9.33 mL of dichloromethane is introduced dropwise over 10 minutes. After 5 minutes a solution of 1.63 g (7 mmol) N-(2,3-dihydro-1H-inden-2-yl)-5-hydroxypentanamide in 8 mL dichloromethane and 2 mL dimethylsulfoxide is added over the course of 10 minutes. The reaction mixture is stirred for another hour at −80° C. before 5 mL of triethylamine is added and the mixture is allowed to warm up to room temperature. 50 mL of saturated brine solution is added for hydrolysis. The organic phase is separated, extracted three times with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:32][C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:9]4[NH:8][CH:12]=[CH:11][CH:10]=4)[S:21][C:20]=13)=[CH:31][CH:30]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(-c5cccn5C(=O)OC(C)(C)C)sc34)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc[nH]5)sc34)ccc2[nH]1
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A mixture of 2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-pyrrole-1-carboxylic acid tert-butyl ester (131 mg, 0.29 mmol) and trifluoroacetic acid (0.1 mL) in dichloromethane (1 mL) was stirred overnight. The solution was diluted with dichloromethane and water, and the pH was adjusted to 8.0 with a saturated aqueous sodium carbonate solution. The organic layer was dried over Na2SO4 and concentrated to afford (2-methyl-1H-indol-5-yl)-[2-(1H-pyrrol-2-yl)-thieno[3,2-b]pyridin-7-yl]-amine (62 mg, 56%). 1H NMR (400 MHz, CD3OD) δ7.93 (d, 1H), 7.25 (m, 3H), 6.93 (dd, 1H), 6.83 (s, 1H, 6.44 (dd, 1H), 6.13 (dd, 1H), 6.07 (s, 1H), 2.37 (s, 3H); RP18-HPLC RT: 5.45 minutes; API MS: 345 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])=[O:16]>O1CCCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:11][N:10]=[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH:25]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1ccccc1NC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1-c1cc(-c2c(Cl)cccc2Cl)no1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.25 g, 5.6 mmol) and 2,2-dichloro-N-(2-ethynylphenyl)acetamide (1.93 g, 8.5 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(2-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a light brown solid, 1.24 g.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C=O)C>[N:22]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF were added K2CO3 and piperidine, followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to 0° C., and water was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][N:28]([S:31](=[O:33])(=[O:32])[NH2:34])[CH2:27]3)=[O:24])=[C:16]2[CH:15]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(N[C@H]1CCNC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Product: NS(=O)(=O)N1CC[C@H](NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)C1

Procedure:
The title compound was prepared by the method substantially similar to that mentioned in Example-98, using 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-pyrrolidin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (Example-82) and Sulfamide to afford the crude, which was purified by Preparative HPLC [Column: 21.2×250×7 um, Zorbax, XDB,C-18(#22), Mobile phase-A: 10 mmol.NH4OAc in water, B:ACN, Gradient (Time/% B): 0/30, 2/30, 8/90 and Flow rate:20 mL/min] to afford 26 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH3:15])[C:10](=[O:12])[N:11]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:5]1[C:4]2[C:3]([S:2][CH3:1])=[N:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH3:15])[C:8]=2[N:7]=[CH:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCOCc1ccccc1
Reactant: CCCn1c(=O)nc(SC)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)nc(SC)c2c1ncn2COCc1ccccc1

Procedure:
After 224 mg (1.0 mmol) of Compound b obtained in Reference Example 2 was dissolved in 2 ml of N,N'-dimethylformamide, 48.0 mg (1.2 mmol) of 60% sodium hydride was added to the mixture under ice cooling. 15 minutes after, 209 μl (1.5 mmol) of benzyl chloromethyl ether was added to the mixture. The mixture was stirred for an hour, poured onto 10 ml of water, and extracted 3 times with 5 ml of chloroform. After washing with a saturated aqueous sodium chloride solution, the extracts were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ether to give 223 mg (yield, 65%) of Compound f as a white powder.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH2:21][C@H:20]([C:35]([OH:37])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:72][O:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[CH:85]([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[CH2:86][NH2:87]>C(Cl)Cl.CC#N>[CH3:72][O:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[CH:85]([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[CH2:86][NH:87][C:35]([C@H:20]1[CH2:21][C@@H:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:23][NH:18][CH2:19]1)=[O:37]
Reactant: COCCCCOc1ccccc1C(CN)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H]2C[C@H](C(=O)O)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: COCCCCOc1ccccc1C(CNC(=O)[C@@H]1CNC[C@H](NS(=O)(=O)c2ccc(C)cc2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice-cooled mixture of (3S*,5R*)-5-(toluene-4-sulfonylamino)-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (208.2 mg, 0.4 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (182 mg, 0.44 mmol) and N-ethyldiisopropylamine (27.4 μL, 0.16 mmol) in CH2Cl2/CH3CN 1:1 (3 mL) is stirred for 10 min. After the addition of 2-[2-(4-methoxy-butoxy)-phenyl]-2-phenyl-ethylamine (119.8 mg, 0.4 mmol), the ice-bath is removed and stirring is continued for 14 h at RT. The reaction mixture is distributed between ethyl acetate and 10% K2CO3 solution. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried over Na2SO4 and evaporated in vacuo. The residue is stirred for 1 h with a freshly prepared mixture of CH2Cl2/piperidine 4:1 (5 mL), evaporated and the residue purified by preparative HPLC (C18 column; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA/20 min, flow 20 mL/min). The combined pure fractions are treated with Na2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a slightly beige amorphous solid. MS: 580.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.61 min.
Reaction SMILES: O.[CH3:2][C:3]1[NH:4][C:5]([CH3:32])=[C:6]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH:7]([CH3:20])[C:8]=1[C:9]([O:11]COC(=O)C(C)(C)C)=[O:10]>C(OC(C)C)(C)C>[CH3:2][C:3]1[NH:4][C:5]([CH3:32])=[C:6]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH:7]([CH3:20])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC1=C(C(=O)O)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
In 30 ml of isopropyl ether saturated with water was dissovled 1.32 g of the bis(pivaloyloxymethyl) 1,4-dihydro -2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in Example 18, and 300 mg of Lipase B was added thereto, followed by stirring at room temperature for 8 horus. Any insoluble matter was removed by filtration and washed with acetone. The filtrate was concentrated under reduce dpressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 741 mg (yield: 76%) of (+)-1,4-dihydro -2,4,6-trimethyl-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[OH:25].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:33][C:34]1[CH:39]=[C:38]([C:2]2[S:23][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:9](=[O:10])[C:4]=3[C:3]=2[CH:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[OH:25])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 85 °C
Yield: 76.4 %

Procedure:
To a solution of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.091 mmol), (3-chlorophenyl)boronic acid (28.7 mg, 0.183 mmol) and aq. 2 M K3PO4 (0.4 mL) in dioxane (2 mL) was added Pd(PPh3)4 (10 mg). The reaction was heated at 85° C. for 2 h, cooled to RT, filtered and the filtrate was diluted DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 3:1) to give 6-(3-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetra hydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 75.6% yield) as a solid. LCMS: [M+-THP-OH] 473 and TR=2.215 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:27]=1[O:34][CH2:35][CH2:36]Cl>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:36][CH2:35][O:34][C:27]4[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:38])=[O:24])[CH2:21][CH2:22]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Reactant: COC(=O)c1cccc(OC)c1OCCCl
Product: COc1cccc(C(=O)O)c1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 14 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 2 g (6 mmol) of 1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.9 g (7.85 mmol) of 2-(2-chloroethoxy)-3-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 14% (0.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27](C)([O-:29])[CH3:28].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH:27]1[CH2:28][O:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1C=CCCc1ccccc1OCc1ccccc1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C(=Cc1ccccc1OCC1CO1)CCc1ccccc1OCc1ccccc1
Yield: 85 %

Procedure:
Following a procedure similar to that described in Example 1(a), 330 mg of 2-[4-(2-benzyloxyphenyl)-1-buten-1-yl)phenol (prepared as described in Preparation 14), 124 mg of potassium t-butoxide and 151 mg of epibromohydrin were reacted in 10 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 328 mg (yield 85%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26]([C:6]3[NH:5][C:4](=[O:7])[NH:3][C:2]=3[CH3:1])=[O:27])=[CH:24][C:23]=2[O:22]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc2c(c1)OCO2

Procedure:
To 5.13 g. of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 7.98 g. of anhydrous aluminum chloride in 80 ml. of nitrobenzene is added dropwise 10.60 g. of 3,4-methylenedioxybenzoyl chloride and the mixture is poured on 500 ml. of 2N-HCl and ice, washed 3 times with ethyl ether, the resulting solid is collected to give the title compound. M.p. 293°-296° C. (dec.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:12][NH:13][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:24][C:19]1[CH:18]=[C:17]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:33]4[CH:34]=[CH:35][C:30]([C:27]([NH2:28])=[O:29])=[CH:31][CH:32]=4)=[CH:8][CH:9]=3)[CH2:14][NH:13][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(Oc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2ccc3c(c2)CNCC3c2ccc(Cl)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 9 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (225 mg, 0.53 mmol), 4-carbamoylphenylboronic acid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water (2 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (19 mg, 7%) as a yellow oil: 1H NMR (CD3OD, 500 MHz) δ 7.96 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.62-7.59 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 4.67-4.53 (m, 3H), 3.82 (dd, J=12.6, 6.1 Hz, 1H), 3.51 (dd, J=12.5, 10.9 Hz, 1H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:5]([OH:26])[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C1C[O:41][CH2:40]C1.C(OC=O)(=O)C.N>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:29]1[CH:28]=[CH:27][C:4]([CH:5]([OH:26])[CH2:6][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]([CH3:18])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:3][C:2]=1[NH:1][CH:40]=[O:41])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1
Reactant: C1CCOC1
Agent: CC(=O)OC=O
Agent: N
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(NC=O)c2)cc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3-amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (100 gms, 0.2 M), toluene 0.2 lit and 0.2 lit THF, were charged in a reactor. The reaction mass was cooled to 15° C. and 35 ml of 3:2 formic acid-acetic anhydride was introduced maintaining temperature below 20° C. The reaction mass was further stirred at 20-30° C. for 1 hour and concentrated under reduced pressure. The residue obtained was dissolved in toluene (0.65 lit) and basified with liquor ammonia. The organic layer was separated, washed with water and concentrated under reduced pressure below 35° C. to yield the title compound. (100 gms, 94.66%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([NH:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:19]1
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
120 μl methansulfonyl chloride were added to an ice cooled suspension of 300 mg trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochloride and 431 μl triethylamine in 5 ml methylene chloride. The reaction mixture was allowed to warm up slowly to rt over night. Then the mixture was diluted with methylene chloride and washed with 10% potassium hydrogen sulfate. The mixture was filtered through a hydrophobic frit and evaporated. The residue was triturated with ether.
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CO[CH2:24][CH2:25]OC.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1.C(B1OB(C=C)OB(C=C)O1)=C>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([O:14][C:13](=[O:19])[NH:12][CH:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([CH:24]=[CH2:25])[C:3]=1[O:20][CH3:21])[CH3:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: COCCOC
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=Cc1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (80 mg, 0.20 mmol) (Example 113, Step 1; peak 2 from chiral separation) in water (0.44 mL) was added 1,2-dimethoxyethane (1.0 mL), potassium carbonate (29 mg, 0.21 mmol), pyridine:trivinylboroxin (1:1) (80 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0092 mmol). The resulting suspension was heated at 80° C. overnight. The reaction was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc once. The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica gel using 0-100% EtOAc in hexane to give the desired compound (68 mg, 100%). LCMS calculated for C12H14ClO (M−NHBoc)+: m/z=209.1. found: 209.0.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16](C)P(=O)(N(C)C)N(C)C>>[C:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])#[N:16]
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
5 g (0.016 mol) Methyl 4-iodo-3-nitrobenzoate (Compound IV-1), 1.77 g (0.02 mol) cuprous cyanide and 15 ml hexamethylphosphoric triamide were added into a reaction flask, and heated to 100° C. and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, then extracted with 100 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, separated by column chromatography to obtain methyl 4-cyano-3-nitrobenzoate (Compound II-8), 2.7 g (0.013 mol), yield 80.4%.