Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].N([O-])=O.[Na+].[C:31]([Cu])#[N:32].[C-]#N.[K+]>O.Cl>[C:31]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26])#[N:32]
Reactant: Nc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Product: N#Cc1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a mixture of 1-(4-amino-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (200 mg, 1.0 eq) in H2O (4 mL) and conc. HCl (0.5 mL) was dropped the materials of NaNO2 (1.1 eq) in 1 mL of H2O at 0° C., the mixture was stirred at room temperature for 30 minutes. Then this mixture was added to another flask contained CuCN (9.0 eq), KCN (8.8 eq) and 2 mL H2O at 0° C., maintained stiffing for 5 h. At the end of reaction, FeSO4 aqueous was added to the mixture, filtrated and washed the solid substance with DMSO, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 1-(4-cyano-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (20 mg, 10%). MS (ESI) 357.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.48 (br, 1H), 8.47 (d, J=4.5 Hz, 2H), 7.83 (d, J=4.5 Hz, 1H), 7.79 (bd, 1H), 7.72 (bs, 2H), 7.52 (d, J=4.5 Hz, 1H), 7.45 (t, J=4.5 Hz, 1H), 6.61 (m, 2H), 3.3 (overlap with DMSO-d6, 1H), 3.10-3.25 (m, 1H), 2.70-2.80 (m, 1H), 2.20-2.27 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1ncccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccnc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 31.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methyl-3-pyridylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and ethanesulfonamide (0.052 g, 0.55 mmol), the title compound (0.019 g, 31%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15].[H][H]>C(O)(C)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15]
Reactant: [H][H]
Reactant: COc1c(C)cc(CC=C(C)C)cc1C
Agent: [Pd]
Solvent: CC(C)O
Product: COc1c(C)cc(CCC(C)C)cc1C
Yield: 68.8 %

Procedure:
A solution of 2,6-dimethyl-4-(3-methyl-2-butenyl)anisole (10 l g, 0.05 mol) in isopropanol (20 mL), together with 5% palladium on carbon (0.1 g) was hydrogenated in a Parr apparatus until the theoretical amount of hydrogen had been consumed. The catalyst was removed by filtration and the solvent evaporated to give a clear residue which was fractionated to afford 7.1 g of the desired product, bp 102°-105° C. (2 mm). NMR (CDCl3) δ0.9 (6H, d), 1.1-2.0 (3H, m), 2.2 (6H, s), 2.5 (2H, t), 3.7 (3H, s), 6.85 (2H, s). IR (film) 3000, 1225, 1025, 870 cm-1. MS (m/e) 206 (M+), 149, 150, 135, 191.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 19.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 80 mg, 0.262 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.521 mmol), oxalyl chloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.90 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 8.18 (d, J=6.9 Hz, 2H), 7.85 (m, 2H), 7.75 (s, 3H), 7.41-7.33 (m, 2H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS [M+H]+: 575.16.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:18]C(=O)C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[Cl-].[Na+].O.ClCCl.CO>[F:15][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([CH2:3][OH:2])=[C:6]([OH:18])[CH:7]=[N:8]2
Reactant: COC(=O)c1c(OC(C)=O)cnc2ccc(OC)c(F)c12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(O)c(CO)c2c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
3-Acetoxy-5-fluoro-6-methoxy-quinoline-4-carboxylic acid methyl ester (355 mg, 1.21 mmol, 1.0 eq) is added at 0° C. to a stirred suspension of lithium aluminium hydride (138 mg, 3.63 mmol, 3.0 eq) in tetrahydrofuran (5 mL). After 2 hours stirring at 0° C., brine is used to quench the reaction and the resulting mixture is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is suspended in dichloromethane:methanol (10:1, v/v) and filtered to afford 5-fluoro-4-hydroxymethyl-6-methoxy-quinolin-3-ol as an off-white solid (62 mg, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(N=Cc2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-chlorobenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as pale yellow needle-like crystals (yield 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:6])=[O:7])[CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)N(CCN)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N(CCNC(C)=O)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 48 h
Yield: 46.4 %

Procedure:
To 1 g of N-(2-aminoethyl)N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 215) dissolved in 25 ml of THF are added 0.167 ml of pyridine and 0.22 g of acetic anhydride. After 48 hours at room temperature, the reaction medium is concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 0.505 g of the expected product.
Reaction SMILES: Br[C:2]1[N:3]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([OH:18])[C:16]=2[N:17]=1)[C@@H:4]1[O:10][C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5]1.[CH2:19](N)[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][C@@:4]1([N:3]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([OH:18])[C:16]=3[N:17]=[CH:2]2)[O:10][C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5]1
Reactant: NCCN
Reactant: OC[C@@H]1CC[C@H](n2c(Br)nc3c(O)ncnc32)O1
Product: NCC[C@]1(n2cnc3c(O)ncnc32)CC[C@@H](CO)O1

Procedure:
The product from step 1 can then be reacted with ethylenediamine to give 8-(2-aminoethyl -2',3'-dideoxyinosine (8-AE-ddI) (Reaction B).
Reaction SMILES: Cl.[CH2:2]([NH2:6])[C:3](=[CH2:5])[CH3:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:8][C:7]([NH:6][CH:2]=[C:3]([CH3:4])[CH3:5])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C=C(C)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 13.44 g of methallylamine hydrochloride and 27.3 g of di-tert.-butyl carbonate in 250 ml of dichloromethane at 20° is treated with 25.2 g of triethylamine. The solution is stirred for 1 hour at 20° washed with water and the organic phase is dried and the solvent is removed to give a colourless oil. Flash-chromatography on silica-gel affords pure 3-(N-tert.-butoxycarbonylamino)-2-methyl-prop-2-ene as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=4.83 (2H, m, 2×CH=C), 4.70-4.60 (1H, broad s, exch. D2O, NH), 3.67 (2H, s, CH2N), 1.73 (3H, s, CH3), 1.45 (9H, s, tBu).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:39](=[CH:40][CH:41]=1)[C:38]1[C:12](=[CH:13][C:14]3[C:18]4[CH:19]=[C:20]5[C:33](=[CH:34][C:17]=4[S:16][C:15]=3[CH:37]=1)[C:32]1[C:27](=[CH:28][C:29]([O:35]C)=[CH:30][CH:31]=1)[C:26]1[C:21]5=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.Cl.N1C=CC=CC=1>>[CH:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[C:20]1[C:33]([C:32]3[C:27]2=[CH:28][C:29]([OH:35])=[CH:30][CH:31]=3)=[CH:34][C:17]2[S:16][C:15]3[CH:37]=[C:38]4[C:12]([C:11]5[C:6]([C:5]6[C:39]4=[CH:40][CH:41]=[C:3]([OH:2])[CH:4]=6)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[CH:13][C:14]=3[C:18]=2[CH:19]=1
Reactant: COc1ccc2c(c1)c1ccccc1c1cc3c(cc21)sc1cc2c4ccc(OC)cc4c4ccccc4c2cc13
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)c1ccccc1c1cc3c(cc21)sc1cc2c4ccc(O)cc4c4ccccc4c2cc13
Temperature: 220 °C
Yield: 87.8 %

Procedure:
A mixture of 9.8 g (18 mmol) of 6,14-dimethoxyditriphenyleno[2,3-b:2′,3′-d]thiophene, 31.2 g (270 mmol) of pyridine hydrochloride, was degassed and placed under nitrogen, and then heated at 220° C. for 6 h, the mixture was allowed to cool to room temperature and water was added. The resulting solid was filtered off, washed with water, and dried under high vacuum to give the product (8.2 g, 15.8 mmol, 88%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].[CH3:49][C:50]1[CH:51]=[CH:52][C:53]([Sn](CCCC)(CCCC)CCCC)=[N:54][CH:55]=1>CN(C=O)C.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>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:53]2[CH:52]=[CH:51][C:50]([CH3:49])=[CH:55][N:54]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Yield: 73.5 %

Procedure:
A solution containing the product from Example 92D (0.50 g, 0.703 mmol) in DMF (7 mL) was treated with LiCl (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol), and the product from Example 74A (0.805 g, 2.11 mmol), heated at 100° C. for 16 hours, cooled, filtered through celite®, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in chloroform to give the title compound (0.374 g, 74% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].[H-].[Na+]>CN(C=O)C>[CH3:38][S:39]([CH2:42][CH2:43][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:37][CH:36]=1)[C:8]1[CH:9]=[CH:10][C:11]([S:14]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1)(=[O:41])=[O:40]
Reactant: C=CS(C)(=O)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(NCc3ccc(C)cc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(N(CCS(C)(=O)=O)Cc3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
4-[(4-methyl-benzyl)-amino]-[N,N-bis(4-methoxy-benzyl)]-benzenesulfonamide (1.03 g, 2.6 mmol) was dissolved in 6 mL of DMF at room temperature, to which methylvinyl sulfone (0.175 mL, 2.0 mmol) and sodium hydride (95%, 60 mg, 2.4 mmol) were added. The reaction was stirred at room temperature for 1.5 h, partitioned between ethyl acetate and water, dried over MgSO4 and purified by column chromatography, eluting with 1:4 acetone/hexane, to provide 935 mg of 4-[(2-methylsulfonyl-ethyl)-(4-methyl-benzyl)-amino]-[N,N-bis(4-methoxy-benzyl)]-benzenesulfonamide.
Reaction SMILES: [CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][S:29](O)(=[O:31])=[O:30]>C(Cl)Cl>[CH:1]1([N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:29]([Cl:28])(=[O:31])=[O:30])=[CH:19][C:18]=3[CH3:23])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (−78° C.) solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 19; 2.70 g; 7.41 mmol) in DCM (27 ml) was treated dropwise with a solution of chlorosulfonic acid (2.48 ml; 37.0 mmol) in DCM (2 mL). The reaction mixture was allowed to warm to RT, then it was stirred at RT for 16 hours. The solution was cooled again (−78° C.) and treated with a second aliquot of chlorosulfonic acid (0.99 ml; 14.8 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was cooled to 5° C. and a mixture of ice/water was carefully added.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][CH3:12])[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:6][CH2:5][C:4]([NH:3][C:2]([CH3:1])([CH2:11][CH3:12])[CH2:7][OH:8])([CH3:10])[CH3:9]
Reactant: CCC1(C)NC(C)(C)COC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(C)(CO)NC(C)(C)CO
Yield: 80 %

Procedure:
In a manner analogous to that described in example 3A hereinabove, 3-methyl,3-ethyl-5,5-dimethyl-2-morpholone is reduced with LiAlH4 to provide a better than 80% yield of (1-hydroxy-2-methyl-2-propyl)(1-hydroxy-2-methyl-2-butyl)amine which has a bp of 136°-7° C./4 mm Hg.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][N:16]=[CH:17]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O=[Pt]=O.O=[Mn]=O>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH2:14][CH2:15][N:16]=[CH:17]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(N2CCC(N3CCCC3)CC2)c2ccncc2c1
Agent: O=[Mn]=O
Agent: O=[Pt]=O
Product: C1=NCCc2c1cccc2N1CCC(N2CCCC2)CC1
Yield: 62.8 %

Procedure:
80A was hydrogenated in the presence of PtO2 and then oxidized with MnO2 to afford 0.85 g (62.8%) of 80B as a yellow oil. MS (ESI) m/z: 284.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][N:7]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])C.O.[OH-].[Li+]>O1CCCC1.O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[N:7][O:6][CH2:5][C:4]([OH:17])=[O:3])[CH3:9])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CON=C(C)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=NOCC(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 37.8 %

Procedure:
To a solution of ethyl({[1-(4-fluorophenyl)ethylidene]amino}oxy)acetate (8.7 g) in a mixture of 50 ml of tetrahydrofuran and 10 ml of water was added, at 20° C., lithium hydroxide monohydrate (2.3 g) and the mixture was stirred at this temperature for 18 hours. Subsequently, the mixture was stirred into ice-cold 10% hydrochloric acid and extracted twice with ethyl acetate (50 ml each time). The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography on silica gel with a solvent gradient from 0:100 methanol/dichloromethane to 60:0 methanol/dichloromethane gave ({[1-(4-fluorophenyl)ethylidene]amino}oxy)acetic acid (2.9 g).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:5][N:4]=[C:2]([CH3:3])[CH:1]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)=NO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetone oxime (4.85 g, 66.4 mmol) was dissolved in THF (100 mL) and cooled to 0° C. n-Butyllithium (1.6M in hexanes, 81 mL, 129.6 mmol) was added and the reaction was stirred at room temperature for 1 hour. 4-Bromo-benzoic acid methyl ester (9.4 g, 43.7 mmol) in THF (30 mL) and the reaction stirred for 24 hours. The mixture was submitted to standard aqueous workup then dried over MgSO4 and evaporated. The residue was taken up in EtOH and HCl (4N in dioxane, 1 mL) was added. The reaction was heated to 60° C. and monitored by analytical TLC. When completed, the reaction mixture was concentrated to dryness to afford the title compound, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) was dissolved in DMSO (20 mL). Sodium tert-butoxide (153 mg, 1.588 mmol) was added followed by 4-methylbenzene-1-sulfonyl chloride (278 mg, 1.456 mmol). The reaction mixture was heated to 50° C. and stirred for 18 hours. Additional 4-methylbenzene-1-sulfonyl chloride (0.5 eq) was added and the reaction mixture was stirred for 18 hours at 50° C. The reaction mixture was subsequently quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (68 mg, 14%). ESI-MS m/z [M+H]+ calc'd for C16H17ClN4O3S, 381.07. found 381.3.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C([NH:29][CH2:30][CH2:31][NH2:32])(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CN(C)C(=O)C.CO>[NH2:29][CH2:30][CH2:31][NH:32][C:11]1[C:12]([O:14][CH3:15])=[C:13]2[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:17]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1c(NCCN)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 120 °C
Reaction time: 24 h
Yield: 58848.5 %

Procedure:
To a solution of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7-difluoro-8-methoxy-3-quinoline carboxylic acid (1.0 g) in N,N-dimethylacetamide (10 ml), N-BOC-ethylenediamine (0.82 mg) was added. The mixture was heated at 120° C. for 12 h. Trifluoracetic acid (20 ml) was added and the reaction mixture was stirred at r.t. for 24 h. The solvent was evaporated under reduced pressure. The crude product was dissolved in water (5 ml) and pH adjusted with 20% NaOH to 7. The precipitate obtained was dispersed in MeOH and filtered to give the title compound (1.01 g).