Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:14])=[N:9][CH2:8][CH2:7]2.[OH-].[Na+].[BH4-].[Na+].Cl>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH3:14])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCN=C2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a stirred solution of 3,4-dihydro-6-methoxy-1-methylisoquinoline hydrochloride (19.2 g, 0.09 m) and NaOH (2.0 g, 0.05 m) in absolute methanol (600 ml) was added NaBH4 (14.0 g, 0.37 m) and the mixture was stirred for 2 hours. Another 4 g (0.11 m) of NaBH4 was added, and after 4 hours the reaction was added slowly to 150 ml of 20% aq HCl. The mixture was brought to gentle reflux for 2 hours and then the reaction was filtered, and the filtrate was concentrated on a rotating evaporator. The residue was added to 400 ml water and basified with 20% NaOH to a pH of 11-12. The mixture was extracted with methylene chloride (3×200 ml), dried over MgSO4, then concentrated to an oil (21 g). The oil was dissolved in ether (1 liter), and the solution was acidified with HCl gas. The resultant solid was filtered off and dried, giving 15.6 g of 1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline hydrochloride, m.p. 218°-219°. (Yield 73%)
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.21 min, m/z=460.01 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.44 Hz, 1H) 2.75-2.84 (m, 1H) 3.35-3.38 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37 (d, J=8.56 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.45 Hz, 2H) 9.08 (s, 1H) 9.21 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34]C)[O:27]2)=[C:19]([NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.[CH3:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1.C(O)(=O)C>O1CCCC1>[C:39]1([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:37][NH:36][C:19]2[N:18]=[C:17]([CH2:16][NH:15][CH:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][OH:34])[O:27]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCC(NCc2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1), 1-methyl-4-piperidinone (52 mg, 0.46 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The aqueous layer was discarded and the organic layer washed with water (10 ml), separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0.5) increasing in polarity to (85:15:0.75) to give the title compound contaminated with example 1. The mixture was treated with diethyl ether (10 ml) and the solid filtered off. This solid was treated with diethyl ether (10 ml) and then filtered. The diethyl ether filtrates were combined and the solvent removed under reduced pressure to give the title compound (60 mg) as a solid. MS: 589 (MH+).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:48][CH:49]([CH:68]([OH:77])[C:69]1[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=1)[C:50]([N:52]1[CH2:55][C:54]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[CH2:53]1)=[O:51].[OH-].[Na+]>CN(C)C=O>[CH2:64]([O:63][C:54]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[CH2:53][N:52]([C:50]([CH:49]([NH:48][C:16](=[O:18])[CH2:9][CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)[CH:68]([OH:77])[C:69]2[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=2)=[O:51])[CH2:55]1)[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)C(O)c2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(NC(=O)CCc2c[nH]cn2)C(O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
0.2 ml (1.5 mmol) of triethylamine is added to a solution containing 100 mg (0.6 mmol) of desamino-histidine hydrochloride and 180 mg (0.6 mmol) of TBTU in 5 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 200 mg (0.4 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxy-phenyl)propan-1-one trifluoroacetate are added. The reaction medium is stirred for 48 h at ambient temperature and then treated with a 1N aqueous solution of sodium hydroxide and extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by preparative thin layer chromatography (eluent: 90/10 dichloromethane/methanol). 80 mg of N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxy-phenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a beige powder with a yield of 39%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C@H:24]([CH2:26][CH3:27])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@@H:22]([C@@H:24]([CH3:25])[CH2:26][CH3:27])[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:28]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A solution of the product of Example 3E (36.81 g) in methanol (50 mL) was treated with L-iso-leucine tert-butyl ester hydrochloride (30 g, 134 mmol), sodium cyanoborohydride (16.9 g, 268 mmol), and acetic acid (4.6 ml, 80.4 mmol), stirred at 25° C. for 3 hours and concentrated. The concentrate was partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with a gradient starting with 10%-66% ethyl acetate in hexanes to give the title compound (28.44 g, 59% yield).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)=[O:31])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[O:31])=[N:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4cccc(F)c4)nc3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(NC(=O)Nc3cccc(F)c3)nc2)n1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A solution of 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-(3-fluorophenyl)urea (0.0824 g, 0.123 mmol) and trifluoromethanesulfonic acid (TCI) (0.02 mL, 0.225 mmol) in TFA (1 mL) was stirred at rt for 3 h, 50° C. for 3 h, then 75° C. for overnight. Saturated sodium bicarbonate was added slowly to quench the reaction and the resulting precipitate was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni NX 5 micron C18 150×30 mm column (10%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The resulting fraction was concentrated to dryness in vacuo. Saturated sodium bicarbonate was added to the residue and the resulting yellow precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 1-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-(3-fluorophenyl)urea (0.0305 g, 58% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.89 (s, 1H); 10.49 (br. s., 1H); 9.38 (s, 1H); 8.71-8.83 (m, 2H); 8.29-8.39 (m, 1H); 8.23 (dd, J=9.00, 2.35 Hz, 1H); 7.87 (br. s., 1H); 7.74 (br. s., 1H); 7.47-7.65 (m, 2H); 7.34 (q, J=7.89 Hz, 1H); 7.20 (d, J=8.02 Hz, 1H); 6.92 (dd, J=7.63, 4.69 Hz, 1H); 6.76-6.87 (m, 1H); 2.44 (s, 3H). m/z (ESI, +ve ion) 432.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: CNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 55.6 %

Procedure:
The product from Example 162a (200 mg, 0.65 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (100 mg, 55%).
Reaction SMILES: Cl.Cl[CH2:3][CH:4]1[CH2:7][N:6]([CH:8]([CH3:10])[CH3:9])[CH2:5]1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:8]([N:6]1[CH2:7][CH:4]([CH2:3][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:5]1)([CH3:10])[CH3:9]
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)N1CC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)N1CC(COc2ccc(C3(C#N)CCOCC3)cc2)C1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
3-(chloromethyl)-1-isopropylazetidine hydrochloride (2.8 g, 15.2 mmol), 4-(4-hydroxyphenyl)tetrahydropyran-4-carbonitrile (3.1 g, 15.2 mmol) and potassium carbonate (8.5 g, 61.6 mmol) were combined in DMF (40 ml) and stirred at 500 for 2 hours. Potassium iodide (0.5 g 3.0 mmol) was added and the mixture was stirred at 50° for 18 hours then at 90-95° for a further 5 hours. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate (80 ml) and water (50 ml). The ethyl acetate was washed with saturated NaCl (50 ml) then dried over Na2SO4 and concentrated in vacuo to give a brown semi-crystalline material which was triturated with diisopropyl ether (25 ml) to give the title compound as a beige powder (2.9 g, 60%). 1H NMR (400 MHz, CDCl3) δ7.38 (d, 2H), 6.91 (d, 2H), 4.08 (m, 4H), 3.89 (m, 2H), 3.41 (t, 2H), 3.02 (t, 2H), 2.87 (m, 1H), 2.31 (m, 1H), 2.15-2.00 (m, 4H), 0.94 (d, 6H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[NH:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16](=[O:18])[CH3:17])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:16](=[O:18])[CH3:17])=[CH:27][CH:26]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(Nc3ccc(NC(=O)c4ccc(C(C)=O)cc4)cc3)cc2)cc1

Procedure:
Compound 748 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-acetylbenzoic acid. [M+H]+ calcd for C30H25N3O4: 492.18; found 492.00.
Reaction SMILES: IC.[C:3]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH3:22])=[O:14])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccccc1C(=O)COC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccccc1C(=O)COC(=O)c1ccccc1
Reaction time: 21 h

Procedure:
Iodomethane (55.8 ml) was added to a stirred suspension of 2-(2-aminophenyl)-2-oxoethyl benzoate (109 g) and potassium carbonate (1 )8 g) in dry dimethylformamide (400 ml) at ambient temperature. The mixture was stirred at this temperature for 21hours and then at 40° for 5 hours. The solvent was removed under reduced pressure at 60°, water (100 ml) was added and the mixture extracted with dichloromethane (3×200 ml). The combined extracts were dried over sodium sulphate and the solvent was removed by evaporation to leave a dark oil. The oil was purified by flash chromatography on a silica gel column eluted with dichloromethane to give the novel compound 2-[2(methylamino)phenyl]-2-oxoethyl benzoate, m.p. 85°-87°.
Reaction SMILES: CO[CH:3]=[CH:4][C:5]1[CH:38]=[CH:37][C:8]([O:9][C@@H:10]2[CH2:14][N:13]([C:15]([N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH3:19])=[O:16])[C@H:12]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:11]2)=[CH:7][CH:6]=1.[NH2:39][C:40]1[CH:45]=[C:44]([Cl:46])[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:42][C:41]=1[S:51]([NH2:54])(=[O:53])=[O:52]>C(#N)C>[NH2:50][S:47]([C:43]1[C:44]([Cl:46])=[CH:45][C:40]2[NH:39][CH:3]([CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:9][C@@H:10]4[CH2:14][N:13]([C:15]([N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH3:19])=[O:16])[C@H:12]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:11]4)=[CH:37][CH:38]=3)[NH:54][S:51](=[O:52])(=[O:53])[C:41]=2[CH:42]=1)(=[O:48])=[O:49]
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(C=COC)cc2)C[C@H]1C(=O)OCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(CC3Nc4cc(Cl)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)OCc1ccccc1

Procedure:
The diphenylmethyl ester product from part (c) in acetonitrile is reacted with a solution of 4-amino-6-chloro-1,3-benzenedisulfonamide in acetonitrile according to the procedure of 1(c) to give (cis)-4-[4-[[7-(aminosulfonyl)-6-chloro-3,4-dihydro-1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][C:20]=1[Cl:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([F:14])[CH:16]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1cc(I)ccc1Cl
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCCCCc1ccc(C#Cc2ccc(Cl)c(F)c2)cc1
Reaction time: 12 h

Procedure:
0.2 mmol of Pd(PPh3)2Cl2 and 0.1 mmol of CuI are added to a mixture of 0.01 mol of 4-pentylphenylacetylene, 0.01 mol of 3-fluoro-4-chloro-iodobenzene and 40 ml of diethylamine at room temperature and stirred for 12 hours. After completion of the reaction, the suspension is filtered, and the filtrate is concentrated by evaporation. Purification by chromatography and/or crystallization gives 4-pentyl-3'-fluoro-4'-chloro tolan having C 49.6° I.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CO[CH2:24][Cl:25]>C(=S)=S.Cl[Ti](Cl)(Cl)Cl>[Cl:25][CH2:24][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)[CH2:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)c(CCl)cc1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,6-di-t-butylfluorene (2.00 g, 7.19 mmol) and chloromethyl methyl ether (2.5 ml) in CS2 (15 ml) was added at 0° C. a solution of TiCl4 (0.4 ml) in CS2 (5 ml). The reaction mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and extracted with ether. The ether extract was dried over sodium sulfate and evaporated under vacuum to leave a residue, which was purified by column chromatography (hexane/CH2Cl2=10/1) and crystallization from hot heptanes. The product provided 2-chloromethyl-3,6-di-t-butylfluorene (yield 0.75 g). 1H NMR (CDCl3): δ 7.80 and 7.78 (each d, 1H, 4,5-H), 7.47 (d, 1H, J=8.1 Hz, H8), 7.34 (dd, 1H, J=8.1Hz, J=1.5Hz, H7), 7.31 (d, 1H, 1H, J=1.5 Hz, H1), 4.72 (s, 2H, CH2Cl), 3.87 (s, 2H, H9), 1.41 (s, 18H, t-Bu) and 2,7-dichloromethyl-3,6-di-t-butylfluorene (yield 0.63 g). 1H NMR (CDCl3): δ 7.87 (br s, 2H, 4,5-H), 7.34 (br s, 2H, 1,8-H), 4.75 (s, 4H, CH2Cl), 3.95 (s, 2H, H9), 1.42 (s, 18H, t-Bu) as indicated by the following reaction:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19]
Reactant: CC(C)CCBr
Reactant: CC(C(=O)O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCC(C)(C(=O)O)c1ccccc1
Temperature: 42.5 °C

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (278.57 g, 1.66 mol) in tetrahydrofuran (700 mL) was added 2-phenyl propionic acid (100.0 g, 0.666 mol) over 40 minutes maintaining the temperature below 15° C. The solution was warmed 40-45° C. for 20 minutes, then cooled below 25° C. and 1-bromo-3-methylbutane (156.0 g, 1.03 mol) was added. The reaction mixture was heated to 50° C. for 10 h, then was cooled to RT, and concentrated to a thick sludge. Methyl tert-butyl ether (900 mL) and water (1100 mL) were added, and the layers were separated. The organic phase was extracted with H2O (200 mL). The combined aqueous phases were treated with 3 M HCl (520 mL) to adjust the pH to approximately 2. The product was extracted with ethyl acetate (1000 mL) and the organic layer was concentrated to a thick oil to give the title compound. The crude oil (assayed for 136.99 g of Example 39-1, 95.3% assay yield) was used directly.
Reaction SMILES: COC([C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][C:7]2([CH2:14][O:13][CH2:12][O:11][CH2:10]2)[C:6]1=[O:15])=O.C(N(CC)CC)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C)C(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:5]2[CH2:9][CH2:8][C:7]3([CH2:10][O:11][CH2:12][O:13][CH2:14]3)[C:6]2=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC2(COCOC2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C(Cc2ccc(Cl)cc2)CCC12COCOC2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
In 2-(4-chlorobenzyl)-1-oxo-7,9-dioxaspiro[4.5]decane-2-carboxylic acid methyl ester (4.0 g, 0.0118 mol), N,N-dimethylacetamide (4 mL), triethylamine (0.15 mL, 0.0118×0.1 mol), and triethylamine hydrochloride (1.79 g, 0.0118×1.1 mol) were added and stirred at 120° C. for 4 hours. In the reaction liquid, toluene and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using toluene, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][C:6]=1I.[O-]S([O-])=O.[Na+].[Na+]>CCO.O>[I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c[nH]1
Yield: 78.6 %

Procedure:
To a suspension of (S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (6) (18.0 g, 36.8 mmol) in 800 mL EtOH/H2O (v/v=30:70) solution was added Na2SO3 (39.4 g, 312.9 mmol). The mixture was refluxed for 17 h. EtOH was evaporated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with brine and dried over Na2SO4 and then concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc=3:1 (v/v)) to afford (S)-tert-butyl 2-(4-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (7), (10.5 g, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 1.16 (s, 5H), 1.38 (s, 4H), 1.80-1.91 (m, 3H), 2.08-2.18 (m, 1H), 3.30-3.46 (m, 2H), 4.66-4.76 (m, 1H), 7.16 (d, 1H, J=14 Hz), 12.04-12.09 (m, 1H) ppm; LC-MS (ESI): m/z calcd 364.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[C:4](Cl)[N:3]=1.CCN(CC)CC>C1COCC1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3[nH]ccc3c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nccc(Oc2ccc3[nH]ccc3c2)n1

Procedure:
A solution of 1.00 g (3.84 mMol) 5-(2-amino-6-chloro-pyrimidin-4-yloxy)-1H-indole (Step 24.1) and 562 μl (4.0 mMol) Et3N in 170 ml THF is hydrogenated in the presence of 0.7 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residue dissolved in EtOAc and H2O. The aqueous layer is extracted twice with water. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 4:1) gives the title compound: MS: [M+1]+=227; TLC(EtOAc/hexane 4:1): Rf=0.4; HPLC: AtRet=8.5.