Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]3[O:17][C@@:18]45[CH2:28][CH2:27][C@H:26]([OH:29])[C:25]([CH3:31])([CH3:30])[C@@H:24]4[CH2:23][CH2:22][C@H:21]([CH3:32])[C@@:19]5([CH3:33])[CH2:20][C:13]=3[C:12]([O:34][P:35]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:36])=[CH:11][C:10]=2[C:9]1=[O:51])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:29][C@@H:26]1[C:25]([CH3:31])([CH3:30])[C@H:24]2[C@@:18]3([O:17][C:14]4[C:15]5[CH2:16][NH:8][C:9](=[O:51])[C:10]=5[CH:11]=[C:12]([O:34][P:35]([O:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([O:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:36])[C:13]=4[CH2:20][C@:19]3([CH3:33])[C@@H:21]([CH3:32])[CH2:22][CH2:23]2)[CH2:28][CH2:27]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OP(=O)(Oc4ccccc4)Oc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OP(=O)(Oc4ccccc4)Oc4ccccc4)cc4c2CNC4=O)C[C@]13C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a solution of the above Compound (56a) (256 mg, 0.36 mmol) in 2.5 ml of dry dichloromethane were added 50 μl of anisole and 2.5 ml of trifluoroacetic acid, and the mixture stirred for 10 min at the same temperature, and then for one hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was made basic with 7% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (silica gel 15 g; ethyl acetate) to give 203 mg (91%) of Compound (57a).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][C@@H:7]([NH2:12])[C@@H:6]([NH2:13])[CH2:5]1.Cl.CO[C@@H]1[C@H](OC)C[C@@H](N)[C@@H](N)C1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44](OC1C=CC([N+]([O-])=O)=CC=1)=[O:45])=[CH:38]2>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:44]([NH:12][C@@H:7]1[CH2:8][C@H:9]([O:10][CH3:11])[C@H:4]([O:3][CH3:2])[CH2:5][C@@H:6]1[NH2:13])=[O:45])=[CH:38]2
Reactant: CO[C@H]1C[C@@H](N)[C@@H](N)C[C@H]1OC
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cc2cc(Cl)ccc2[nH]1
Agent: CO[C@H]1C[C@H](N)[C@H](N)C[C@H]1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture (645 mg) of (1R*,2S*,4R*,5S*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride and (1R*,2S*,4S*,5R*)-4,5-dimethoxy-1,2-cyclohexanediamine hydrochloride was suspended in N,N-dimethylformamide (50 ml), and triethylamine (1.10 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (920 mg) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with dichloromethane. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:9) to obtain a mixture (330 mg) of (1R*,2S*,4R*,5S*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine and (1R*,2S*,4S*,5R*)-N1-[(5-chloroindol-2-yl)carbonyl]-4,5-dimethoxy-1,2-cyclohexanediamine as pale yellow powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:50][CH3:51])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH3:26])CCN3CCOCC3)=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)[CH3:2].CN[CH2:54][CH2:55][OH:56]>>[CH2:1]([N:3]([CH2:50][CH3:51])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH2:54][CH2:55][OH:56])[CH3:26])=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CNCCO
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCO)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide Example 131, using 2-(methylamino)ethanol in place of N-methyl-2-morpholinoethanamine. MS (ES, m/z): 620.32 [M+H]+.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:40][C:41]3[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:43][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[O:21][C:22]3[C:23]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:24][C:25]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 1.16 grams of 4,4'-isopropylidenebisphenol (0.005 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.24 gram (0.01 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4-iso-propylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,4,6-tri-t-butylphenyl) phosphorochloridite (6.0 grams, 0.01 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,4,6-tri-t-butylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 4.87 grams. The molecular weight, FD/MS was 1332.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([NH2:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:30](OC(OCC)OCC)C>C1(C)C=CC=CC=1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=[C:10]3[C:8](=[O:9])[N:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:30]=[N:15][C:14]=23)=[CH:21][CH:20]=1
Reactant: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide (1-10A-1a, 200 mg, 0.46 mmol) and triethylorthoformate (116 microliters, 0.7 mmol) in toluene (2.5 ml) was heated at 100° C. for 0.45 h and at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with 1 M K2CO3 and saturated aqueous brine, dried, and concentrated under vacuum. The crude residue was purified via radial chromatography (1 mm plates, 50% EtOAc/hexanes as eluant) to give the desired product 10A-1 as an amorphous solid: MS 442.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.53-7.50 (m, 1H), 7.47-7.39 (m, 3H), 7.35-7.28 (m, 4H), 4.25 (bm, 2H), 3.95 (bm, 2H), 3.75 (bm, 2H), 3.00 (bm, 2H).
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH:40]=[CH2:41]>O>[Cl:1][OH:2].[CH2:41]([N:19]1[CH2:18][CH2:17][C@:15]23[C:16]4[C:3]5[O:2][C@H:14]2[C:13](=[O:20])[CH2:12][CH2:11][C@@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:9]1[CH2:8][C:7]=4[CH:6]=[CH:5][C:4]=5[O:31][CH3:32])[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Product: OCl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (2.00 g, 4.76 mmol), potassium carbonate (4.00 g, 28.9 mmol) and allyl bromide (0.56 ml, 6.62 mmol) in water-free N,N-dimethylformamide (15 ml) was stirred for 7 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 50 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 300 ml dichloromethane, washed with water (3×200 ml) and saturated sodium chloride solution (4×200 ml), dried over sodium sulphate and evaporated down. The obtained brown oil was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 50 ml ether and precipitated by the addition of etherial HCl up to the acid reaction. The product was recrystallised from isopropanol. Yield: 1.50 g (69%) of the compound 1.HCl as colourless crystals. Fp. 129-130° C.; MS (CI): 460 (M++1); IR (KBr): 1725 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.98 (s, wide, HN+), 7.30-7.18 (m, 5 arom. H), 6.89 (d, 1 arom. H, J=8.4 Hz), 6.83 (d, 1 arom. H, J=8.4 Hz), 5.89 (m, 1 olef. H), 5.69 (m, 2 olef. H), 4.94 (s, CH-5), 3.81 (s, CH3O).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][CH:9]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1csc(Br)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cscn1
Yield: 84.8 %

Procedure:
A solution of 4-acetamido-2-bromo-thiazole (22 g., 0.2 m) and sodium acetate (8.2 g, 0.1 m) in methanol (600 ml) was hydrogenated at room temperature and 1 atm. pressure oven 10% palladium on carbon (5 g) until the theoretical uptake of hydrogen had occurred (about 3 hours). The catalyst was removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was extracted with carbon tetrachloride (200 ml) in a Soxlet apparatus. The extract was cooled and the crystals removed by filtration to yield 4-acetamidothiazole (12 g, 78%). m.p. 176° C. Found: C, 41.8; H, 4.3; N, 19.3. C5H6N2OS requires: C, 42.2; H, 4.3; N, 19.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].Br[CH2:14][CH2:15][O:16][C:17]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:31][CH3:32].[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][NH:34]1.FC(F)(F)C(O)=O>N.CO.ClCCl>[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][N:34]1[CH2:14][CH2:15][O:16][C:17]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][C:20]([CH:21]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:18]=1[O:31][CH3:32]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc(C=O)cc(-c2ccccc2)c1OCCBr
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=NNC(=O)c2ccc(O)c(Cl)c2)cc(-c2ccccc2)c1OCCN1CCc2ccccc2C1

Procedure:
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin—[building block 1]) (2 g, ˜2 mmoles), 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde ([building block 2]) (0.93 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and dichloromethane (1:12). This afforded 0.31 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)=[O:7].[C:17]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([C:11]([NH:34][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:28][CH2:29]2)=[O:13])[CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1cccc(C(=O)CCCCO)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(CCCCO)c1cccc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Reaction time: 16 h

Procedure:
A solution of 8-2 (0.44 g, 2 mmoles) in DMF (25 ml) was treated with N-(CBZ-4-piperidinyl)methyl amine (0.53 g, 2 mmoles) (8-3), HOBT (0.3 g, 2.2 mmoles) EDC (0.44 g, 2.3 mmoles) followed by NMM (0.4 g, 4 mmoles) and the resulting solution was stirred for 16 hours. The solvent was removed and the residue was taken up in H2O and extracted with EtOAc. The organic extract was washed with 10% KHSO4 solution, brine, saturated NaHCO3 solution, brine and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (97)/MeOH(3) to give pure 8-4. Rf 0.35 (silica, CHCl3 (95)/MeOH(5). ##STR55##
Reaction SMILES: [C:1]1(=[O:11])O[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([NH:18][NH2:19])(=[O:17])[C:13]([NH:15][NH2:16])=[O:14].[CH3:20][S:21]([CH3:23])=[O:22].[OH2:24]>C1(C)C=CC=CC=1>[C:4]1(=[O:5])[N:16]([NH:15][C:13]([C:12]([NH:18][N:19]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:5])=[O:17])=[O:14])[C:1](=[O:24])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12.[CH3:20][S:21]([CH3:23])=[O:22]
Reactant: O
Reactant: NNC(=O)C(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(NN1C(=O)c2ccccc2C1=O)C(=O)NN1C(=O)c2ccccc2C1=O

Procedure:
Two moles of phthalic anhydride (296 g.) and one mole of oxalic dihydrazide (118 g.) in 500 ml. dimethyl sulfoxide and 750 ml. toluene were heated at reflux until two moles of water were removed (about two hours). The mixture was cooled and filtered. After washing with benzene, the white product was dried to constant weight at 50° C. giving an essentially quantitative yield of N,N'bis(phthalimido)oxamide-dimethyl sulfoxide 1:2 complex.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20]C(=O)C)[CH:17]=[CH:18][CH:19]=1.CS(C1C=CC(CNC)=CC=1)(=O)=O.C([O-])C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Agent: CC[O-]
Agent: CNCc1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1

Procedure:
Acetyl was eliminated from N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 34) by the method described in example 17, intermediate 1, in the presence of sodium ethanolate.
Reaction SMILES: C(OC(=O)[N:7]([C:18]1[N:23]=[CH:22][C:21]([CH:24]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]([S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:27]=2)O)=[CH:20][N:19]=1)[CH2:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:40]1([S:37]([N:28]2[C:29]3=[N:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[C:34]3[C:26]([CH2:24][C:21]3[CH:22]=[N:23][C:18]([NH:7][CH2:8][C:9]4[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=4)=[N:19][CH:20]=3)=[CH:27]2)(=[O:39])=[O:38])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cnc2c(c1)c(C(O)c1cnc(N(Cc3cc(F)cnc3OC)C(=O)OC(C)(C)C)nc1)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cnc2c(c1)c(Cc1cnc(NCc3cc(F)cnc3OC)nc1)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
To {5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyrimidin-2-yl}-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (124, 1 equivalent) in 10.0 mL of acetonitrile, triethylsilane (15.6 equivalents) and trifluoroacetic acid (16.9 equivalents) are added. The reaction is heated at 80° C. for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound, which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[OH:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc2cc[nH]c2cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110 mg, 0.325 mmol), (prepared as described for the starting material in Example 1), and 6-fluoro-5-hydroxyindole (59 mg, 0.39 mmol), (prepared as described for the starting material in Example 242), in DMF (1.8 ml) containing potassium carbonate (67 mg, 0.487 mmol) was heated at 90° C. for 2 hours. After cooling, water was added. The solid was separated and triturated with methanol. Water was added and the solid was filtered, washed with water and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (55 mg, 41%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O>>[CH:16]1([C:8]2[C:7]([CH2:6][O:5][C:27]3[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:23][C:22]=3[F:21])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)OCc1c(C2CCCC2)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2c(C3CCCC3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-cyclopentyl-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ6.89-6.96 (m, 2H), 5.26 (s, 2H), 3.57 (m, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.06-2.12 (m, 2H), 1.81-1.97 (m, 4H), 1.69-1.79 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C19H15F5NO3S, 436.1 (M+H). found 436.1.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[C:20]([CH:34]2[CH2:36][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[C:20]([CH:34]2[CH2:35][CH2:36]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-cyclopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 242, 0.932 g, 1.78 mmol) following the procedure described for Intermediate 21. The desired product was obtained as an orange foam (0.518 g, 68%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[C:29](OC(=O)CC)(=O)[CH2:30]C>>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH:9]([CH2:8][NH:7][C:6](=[O:5])[CH2:29][CH3:30])[O:13]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1

Procedure:
The compound is prepared from {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (232 mg, 0.60 mmol) and propionic anhydride (120 mg, 0.96 mmol) following the method described for Example 5. The crude product is purified by silica gel column chromatography (2% to 5% MeOH in EtOAc) to give the title compound as solid. MS (m/z): 344 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ8.16 (br. t, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.52 (d, J=7.1 Hz, 2H), 7.27 (d, J=7.4 Hz, 2H), 4.97 (d, J=7.4 Hz, 1H), 4.80–4.65 (m, 1H), 4.10 (t, J=7.7 Hz, 2H), 3.94 (t, J=6.9 Hz, 2H), 3.41–3.99 (m, 2H), 2.49–2.47 (m, 2H), 2.09 (q, J=5.8 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).