Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[C@@H:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5](=[O:11])OO1.[CH2:13]1[CH2:17][O:16]CC1.B.[CH2:19]1COCC1>CO>[OH:11][CH2:5][CH2:6][C@H:7]1[O:16][C:17]([CH3:13])([CH3:19])[O:10][C:8]1=[O:9]
Reactant: CC1(C)OOC(=O)[C@@H]1CC(=O)O
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: CC1(C)OC(=O)[C@@H](CCO)O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
To a stirring solution of (R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-acetic acid (15.8 g, 91 mmol), and THF (90 mL), at 0° C., under N2, was added borane-THF complex (1.0 M in THF, 100 mL, 100 mmol) dropwise over 60 minutes. The mixture was stirred at 0° C. for 2.5 hours and then allowed to warm to 25° C. The mixture was stirred at room temperature for 19 hours. The mixture was poured into MeOH (150 mL) and the solution was evaporated to dryness under reduced pressure at 25° C. The residue was purified via silica gel chromatography using 30% EtOAc in hexanes to obtain the desired alcohol as a clear oil (7.1 g, 44.6 mmol, 49% yield). 1H NMR (400 MHz, CDCl3) δ 4.61-4.51 (m, 1H), 3.89-3.80 (m, 2H), 2.20-2.12 (m, 2H), 2.05-1.98 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[C:37]1[CH:52]=[N:51][C:40]2[NH:41][CH:42]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)[NH:43][C:44](=[O:45])[C:39]=2[CH:38]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:37]4[CH:52]=[N:51][C:40]5[NH:41][CH:42]([C:46]6[S:47][CH:48]=[CH:49][CH:50]=6)[NH:43][C:44](=[O:45])[C:39]=5[CH:38]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1NC(c2cccs2)Nc2ncc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)C(=O)NC(c3cccs3)N4)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol), compound 6-bromo-2-(thiophen-2-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (112 mg, 0.36 mmol) and K3PO4.3H2O (239 mg, 0.90 mmol) in 1,4-dioxane (3 mL), Pd(dppf)Cl2 (20 mg) was added under N2 protection. After being stirred at 80° C. overnight, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4-oxo-2-(thiophen-2-yl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)benzofuran-3-carboxamide (40 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.80 (d, J=1.6 Hz, 1H), 8.51 (d, J=4.4 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.95˜8.05 (m, 4H), 7.60 (s, 1H), 7.47 (dd, J=5.2, 1.2 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 7.12 (d, J=2.8 Hz, 1H), 7.00 (dd, J=4.8, 3.2 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 606
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)OC2)C1=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:43][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:37])[C:13]3=[O:21]
Reactant: COCCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: COCCOCCN1C(=O)C2(COc3cc(OCCOC)ccc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (94%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6) δ7.32-7.27 (m, 1H), 7.12 (d, J=7.2 Hz, 1H), 7.07-6.98 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.76 (dd, J=8.7, 2.6 Hz, 1H), 6.32 (d, J=2.6 Hz, 1H), 4.78 (ABq, 2H), 4.08-3.88 (m, 4H), 3.82-3.74 (m, 2H), 3.68-3.59 (m, 4H), 3.52-3.47 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CC)=O.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:18]([C:3]1[N:4]([CH3:17])[S:5](=[O:15])(=[O:16])[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[C:2]=1[OH:1])=[O:20]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nc3ccccc3s2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 70 %

Procedure:
Prepared analogous to Example 1 from ethyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-benzothiazole with a yield of 70% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:18]=[CH:17][O:16][CH:15]=1)=[O:13].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C.CCCCCC>[C:19]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:18]=[CH:17][O:16][CH:15]=1)=[O:13])(=[O:21])[CH3:20]
Reactant: Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2ccoc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(3-furoyl)indole (Example 79) and acetyl chloride. m.p.:217-219° C. (ethyl acetate/hexane)
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[CH2:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:2][C:3]#[C:4][CH3:5])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC#CCBr
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCN1CCC(Cc2ccccc2)CC1
Yield: 44 %

Procedure:
A mixture of 1-bromobut-2-yne (1.19 g, 9.00 mmol), 4-benzylpiperidine (1.58 g, 9.00 mmol) and K2CO3 (2.5 g, 18 mmol) in 25 mL of CH3CN was refluxed for 12 hr. The mixture was filtered and was washed with EtOAc (3×30 mL). The filtrate was evaporated in vacuo and was purified by flash chromatography to give the product as a colorless oil (0.9 g, 50%): 1H NMR (CDCl3) d 1.31 (m, 2 H), 1.60 (m, 1 H), 1.63 (m, 2 H), 1.81 (s, 3 H), 2.04 (m, 2 H), 2.52 (d, J=9.9 Hz, 2 H), 2.88 (m, 2 H), 3.16 (s, 2 H), 7.15-7.27 (m, 5 H); HRMS calcd for C16H21N 227.1670, found 227.1670.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].[H-].[Na+].Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(C#N)cccc21
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Prepared using General Procedure 9. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-9 (3.0 g, 1.16 mmol) in DMF (20 mL) was added NaH (1.39 g of 60% dispersion in mineral oil, 34.8 mmol) at 0° C. with stirring for 3 h before the addition of 2-chloro-N,N-dimethylacetamide (2.82 g, 23.2 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and then warmed to room temperature for 1 h. The reaction mixture was quenched with water (3 mL) slowly at 0° C. The mixture was partitioned between EA (3×20 mL) and water (50 mL). The combined organic layers were concentrated and purified by chromatography (DCM/MeOH) to provide product 3.82 g (96.0%) of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate as a light brown solid. LCMS-ESI (m/z) calculated for C19H25ClN6O6; 343.4; found 366.1 [M+Na]+, tR=3.16 min.
Reaction SMILES: [CH3:1][CH:2]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C.[Br:22][C:23](C)([CH3:27])[C:24](Br)=[O:25]>C1(C)C=CC=CC=1>[Br:22][CH:23]([CH3:27])[C:24]([O:14][C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:1])=[O:25]
Reactant: CCCCCCCCCCCC(C)O
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(CCCCCCCCCCC)OC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a stirred solution of tridecan-2-ol 68 (5 g, 24.9 mmol) in toluene (50 mL) was added triethylamine (3.5 mL, 27.45 mmol)) and followed by 2-bromo-2-methylpropionyl bromide 97 (6.31 g, 27.45 mmol) at 5-10° C. The reaction mixture was stirred for 3 hour at 55-60° C., and the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated. The organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 98 (8.1 g, yield: 96%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:18][CH3:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: CCC1C(=O)N(CC)CCc2c1ccc(N)c2OC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCC1C(=O)N(CC)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3C(=O)NC)n1)c2OC

Procedure:
Prepared in the same manner as Example 151 from 7-amino-1,3-diethyl-6-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (85 mg, 0.32 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.36 mmol) to yield 2-[5-Chloro-2-(1,3-diethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow powder. MP: 157-158° C.; 1H-NMR (CDCl3) δ 11.01 (s, 1H), 8.65 (d, J=8.6 Hz, 1H), 8.09 (d, J=17.3 Hz, 2H), 7.50-7.35 (m, 3H), 7.08 (t, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.28 (br s, 1H), 3.96-3.80 (m, 5H), 3.60-3.40 (m, 4H), 3.12-2.91 (m, 5H), 2.21 (p, J=7 Hz, 1H), 1.90 (p, J=7 Hz, 1H), 1.09 (m, 6H); LC/MS (ESI+): 523 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)[OH:10].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(O)c1

Procedure:
In these examples and comparative examples, ethylbenzene was sulfonated with sulfuric acid in the presence of anhydrous sodium sulfate, isomerized, hydrolyzed (desulfonated), separated from excess sulfuric acid, neutralized and fused with an alkali to give m-ethylphenol. The composition of the reaction mixture in each step was examined, and the relationship with the quantity of sodium sulfate was investigated.
Reaction SMILES: [C:1]1([C:7]2[C:22](=[O:23])[NH:21][C:10]3=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:31][C:32]1[N:33]([CH3:37])[N:34]=[CH:35][N:36]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:22]([O:23][CH2:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][N:36]=3)=[N:21][C:10]3=[C:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(-c3ccccc3)nncc2cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncc2cc1-c1ccccc1

Procedure:
3,8-Diphenyl-1H-pyrido[2,3-d]pyridazin-2-one (40 mg), cesium carbonate (174 mg) and 3-(chloromethyl)-2-methyl-2H-[1,2,4]triazole (prepared using the conditions described in EP-A-0170073) (27 mg) were stirred together at room temperature in DMF (4 ml) under nitrogen overnight. Water (25 ml) was added and the resultant solution was washed with dichloromethane (3×25 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane. The product was recrystallised froim diethyl ether/ethanol/ethyl acetate, yielding 3,8-diphenyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrido[2,3-d]pyridazine as a white solid (8 mg). Data for the title compound: m.p. 222-223° C. 1H NMR (400 MHz, CDCl3) δ3.62 (3H, s), 5.67 (2H, s), 7.48 (3H, m), 7.56 (3H, m), 7.63 (2H, m), 7.85 (1H, s), 8.13 (2H, m), 8.20 (1H, s), 9.49 (1H, s); MS (ES+) m/e 395 [MH]+.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.389 g, 4.16 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed toluene (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH2:34])[N:27]=1>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:22]([NH:21][S:18]([CH2:17][C:8]2[C:7]([S:4]([N:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:20])=[O:19])=[O:23])[N:27]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
A solution of the sulfonyl isocyanate from Example 16 (approximately 1.3 g) and 0.56 g of 4,6-dimethoxy-2-aminopyrimidine in 6 ml methylene chloride was stirred overnight at room temperature. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Trituration of the residue with warm n-butyl chloride/ethyl acetate gave a cream-colored solid. The yield of the title compound, m.p. 175°-180°, was 1.1 g; IR(nujol): 1720, 1730 cm-1 ; NMR(CDCl3 /DMSO-d6): δ 2.8 (6H, s, SO2N(CH3)2), 3.7-4.0 (9H, s, CO2CH3 and OCH3 's), 5.8-6.0 (3H, two singlets, --CH2 -- and heterocyclic ring H), 7.55-8.4 (3H, m), 10.5 (1H, br s, NH), 12.5 (1H, br s, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>C(OCC)C>[Br:16][CH2:10][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:11]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)c1c(F)cccc1F
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15° C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%).
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[CH2:1]([NH:11][C:26]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 5.4 ml (0.027 mol) of decylamine and 5.6 ml (0.04 mol(of triethylamine in 20 ml of methylene chloride cooled in an ice bath was added dropwise a solution of 5.0 g (0.027 mol) of 4-nitrobenzoyl chloride in 40 ml of methylene chloride. The reaction mixture was stirred in the ice bath for 30 minutes, at room temperature for 15 minutes and kept at 0° for 18 hours. After dilution was methylene chloride, the mixture was washed with 0.5 N NaOH and the extract was dried and concentrated to a solid. Recrystallization from methylene chloride-hexane gave 8.1 g (98% yield, mp 89°-91°) of 4-[(decylamino)carbonyl]nitrobenzene. The nmr was consistent with the structure.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[N:22]#[C:23]Br.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([C:5]2[O:6][C:23]([NH2:22])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: N#CBr
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(I)ccc1Nc1c(-c2nnc(N)o2)ccc(F)c1F
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806 g, 2 mmol) in 5 ml of dioxane was added cyanogen bromide (0.212 g, 2 mmol) followed by a solution of sodium bicarbonate (0.17 g, 2 mmol) in 5 ml of water. The resulting mixture was stirred 18 ours at room temperature. The solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1) to give the product which was recrystallized from ethyl acetate/hexanes to provide a pale-yellow crystal. The yield: 58% m.p. 183.7-184.0° C. 1H NMR(CDCl3, 400 Hz): /ppm 8.87(1H, s, —NH—); 7.52(1H, s, Phenyl-H); 7.45-7.49(1H, m, Phenyl-H); 7.40(1H, d, J=8.3 Hz, Phenyl-H); 6.77-6.83(1H, m Phenyl-H); 6.60-6.63(1H, m, Phenyl-H); 5.02(2H, s, —NH2), 2.36(3H, s, CH3)
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]([C:11]2[C:12](=[O:31])[NH:13][C:14]3[C:19]([C:20]=2[NH:21]CC2C=CC(OC)=CC=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=CC=1>C(O)(C(F)(F)F)=O>[NH2:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:31])[C:11]=1[C:9]([NH2:8])=[O:10]
Reactant: COc1ccc(CNc2c(C(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)c(=O)[nH]c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(N)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 249.5 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Example 74a) (2.0 g, 3.55 mmol) was dissolved in TFA (15 mL) and the solution was stirred at room temperature for 6 hours. The TFA was removed under vacuum, and the resultant solid was stirred in water overnight, then collected by filtration to give 1.8 grams of crude final product. 1H NMR (400 MHz, DMSO-d6) δ 7.18 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 8.09 (d, J=7.6 Hz, 2H), 9.83 (d, J=4.8 Hz, 1H), 10.85 (bs, 1H), 11.12 (s, 1H). MS 204 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:9][C:10]1[C:19]([C@H:20]2[CH2:24][CH2:23][O:22][C@H:21]2[CH2:25][OH:26])=[CH:18][CH:17]=[C:16]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([NH:9][C:10]1[C:19]([C@H:20]2[CH2:24][CH2:23][O:22][C@H:21]2[CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][CH:17]=[C:16]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[CH3:7]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2CO)c1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2COS(C)(=O)=O)c1NC(C)=O

Procedure:
Methanesulfonyl chloride (0.042 mL) was added to a mixture of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(hydroxymethyl)-tetrahydrofuran-3-yl]benzoate (Intermediate 32, 0.14 g) and triethylamine (0.15 mL) in DCM (5 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was washed with 1M hydrochloric acid, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(methanesulfonyloxymethyl)-tetrahydrofuran-3-yl]benzoate (0.166 g) as a gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:23][C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: COc1cccc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)C2CSC(c3cccnc3)N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of 630 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 350 mg of m-anisidine, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed with two portions of water, and then with aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by preparative thin layer chromatography to give 230 mg of N-(3-methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 250 mg of N-(3-methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 129° C.