Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[S:54][CH:55]=1)\[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:28]([CH2:31][Cl:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:84])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[S:54][CH:55]=1)\[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:34])=[C:28]([CH2:31][Cl:32])[CH2:29][S:30](=[O:84])[C@H:25]12)=[O:22])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
23.4 g (22.3 mmol) of benzhydryl 7-[(Z)-2-(benzhydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 500 ml of methylene chloride, and 4.8 g (22.3 mmol) of m-chloroperbenzoic acid was added over a period of 10 minutes under cooling with ice. The mixture was stirred for further 20 minutes. After an addition of 150 ml of a 10% sodium thiosulfate aqueous solution, the reaction solution was subjected to liquid separation. The organic layer was washed with a 5% sodium bicarbonate aqueous solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a powder of the above identified compound (the powder was used to the subsequent reaction without purification).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[F:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([Cl:21])=[O:12]
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Temperature: 60 °C

Procedure:
A suspension of 3-(2-fluorocyclopentyloxy)-4-methoxybenzoic acid (0.48 g) in toluene (20 mL) is treated with thionyl chloride (0.34 g) and then is heated at 60° C. for 3 hours, and cooled and evaporated to give 3-(2-fluorocyclopentyl-oxy)-4-methoxybenzoyl chloride.
Reaction SMILES: [N:1]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][CH2:20][C:21]([NH:23][C@@H:24]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH2:53])=[O:52])[CH2:47][CH2:48][S:49][CH3:50])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>C(SC)C.C(S)(S)C>[NH:1]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][CH2:20][C:21]([NH:23][C@@H:24]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH2:53])=[O:52])[CH2:47][CH2:48][S:49][CH3:50])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Agent: CCSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-GlyOH (1.00 g.) and HDTrp-Leu-MetNH2 trifluoroacetate salt (1.10 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-Gly-DTrp-Leu-MetNH2 in 36% yield. De-t-butoxycarbonylation of BocPro-DTrp-Gly-DTrp-Leu-MetNH2 (0.68 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HPro-DTrp-Gly-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (2:3) salt in 59% yield.
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN(C)[C:16](=[O:18])[CH3:17]>CCOCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:16](=[O:18])[CH3:17])=[N:8][CH:9]=1
Reactant: CC(=O)N(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(=O)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
sec-BuLi (1.9 mL, 1.4 M in hexane) was added drop wise to a solution of 2-bromo-5-fluoropyridine (500 mg, 2.8 mmol) in dry Et2O (6 mL) at −78° C. Stirring was continued at this temperature for 10 minutes, after which a solution of N,N-dimethylacetamide (290 μL, 3.1 mmol) in dry Et2O (1 mL) was added drop wise. Stirring was continued at −78° C. for 1 h, where after the reaction mixture was allowed to slowly reach rt. The reaction mixture was again cooled to −78° C. and was quenched by adding 1M HCl aq. solution (6 mL) before it was left to warm to rt over night. The water and organic phases were separated and the water phase extracted with Et2O (2×10 mL). Combined organics were washed with water and brine and dried (MgSO4). After filtration and Careful! evaporation (the title compound is volatile) the red/brown oily crude was dissolved in CH2Cl2 and a small amount of SiO2 was added. The suspension was filtered through a pad of Celite and the solvent was removed by evaporation to give the title compound (203 mg, 1.5 mmol, 52%) as an orange oil. The product was considered to be pure enough to be used directly in the next step without prior purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)Cc1ccccc1-c1ccccn1
Product: O=C(Cc1ccccc1-c1ccccn1)N[C@H]1CCN(CCc2ccccc2)C1

Procedure:
2-(2-pyridyl)phenylacetic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-2-(2-pyridyl)phenylacetamide.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28]O)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:2][S:1]4=[O:3])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: OCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1OCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sulfonyl chloride (0.63 g, 5.3 mmol) in THF (2 ml) is added within 5 minutes to a solution of 2-{4-(2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-ethanol (1.50 g, 4.4 mmol) and triethylamine (3.0 ml, 22 mmol) in absolute THF (20 ml) at +5° C. After stirring the resulting suspension for four hours at room temperature it is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 202–203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:24][C:25]([CH:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:32]1[CH2:31][CH2:30][N:29]([CH:27]([C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])[CH3:28])[CH2:34][CH2:33]1)=[O:9]
Reactant: CCCCCCNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.39 g of 3,4,5-trimethoxycinnamoyl chloride is added with stirring at room temperature to a solution of 5.00 g of 1-[1-(hexylaminocarbonyl)ethyl]piperazine in 80 ml of chloroform, and the resulting solution is stirred at room temperature for 15 minutes.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([NH2:9])=[O:8])=[CH:5][N:6]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([O:10][C:2]2[S:3][C:4]([C:7]([NH2:9])=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:13]=1)=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)s1

Procedure:
Dissolve 2-chlorothiazole-5-carboxamide (0.771 g, 4.78 mmol) and 4-hydroxybenzaldehyde (0.584 g, 4.78 mmol) in DMF (15.9 mL). Add K2CO3 (1.651 g, 11.95 mmol) and heat at 100° C. for 2 hours. Concentrate the reaction mixture. Take the solid up in dichloromethane:methanol (5:1). Add ethyl acetate to precipitate out a white solid. Filter and collect the solid as the title compound: 1H NMR (DMSO): 10.00 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.41 (s, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.4 min, 98.2% purity.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[N:28]([CH3:30])[CH3:29])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([NH2:39])=[O:38])[CH2:32]1>O1CCOCC1>[CH3:29][N:28]([CH3:30])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:31]3[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([NH2:39])=[O:38])[CH2:32]3)[N:11]=2)[CH2:14][CH2:15]1
Reactant: NC(=O)C1CCCNC1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Solvent: C1COCCO1
Product: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(N3CCCC(C(N)=O)C3)nc3ccccc23)CC1

Procedure:
Compound 47 (50 mg, 0.12 mmol) and piperidine-3-carboxamide (45 mg, 0.36 mmol) in 1,4-dioxane (5 mL) were heated to 117° C. for 24 h in a sealed tube. The product (AGN-219171) was purified by basic alumina flash column chromatography using 3% MeOH and 97% CH2Cl2 solution as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.Cl[CH2:23]CN1CCCCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:23][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCCCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of N-(2-chloroethyl)piperidine hydrochloride. The product is obtained as a pale yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:34][C:35]1([N:39]([CH3:41])[CH3:40])[CH2:38][NH:37][CH2:36]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:37]5[CH2:38][C:35]([CH3:34])([N:39]([CH3:41])[CH3:40])[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN(C)C1(C)CNC1
Agent: CS(=O)(=O)O
Product: CN(C)C1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 75.6 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate. 1.55 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 268° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]3)(=O)=O)=CC=1>CN(C=O)C.O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([NH:14][CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]4)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCCNc3nnc(-c4ccc(C(F)(F)F)cc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.5 %

Procedure:
To a solution of 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.047 g, 0.207 mmol) in DMF (2 mL) was added potassium carbonate (0.052 g, 0.376 mmol) and 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethyl 4-methylbenzenesulfonate (0.068 g, 0.188 mmol) and the reaction stirred at room temperature for 15 h. The temperature was then increased to 60° C. for 15 h. After cooling to room temperature, the mixture was diluted with water (5 mL), extracted with EtOAC (20 mL), dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC on a X— Terra column (10×150 mm, 5 μm) with 0-100% AcCN in 10 mM aq. NH4OAc. Solvents were evaporated under vacuum to yield 6-(2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-ylamino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (4.3 mg, 5.5%). 1H NMR: 400 MHz, DMSO-d6: δ 2.53 (dd, J=7.60, 8.40 Hz, 2H), 2.91 (t, J=8.00 Hz, 2H), 3.76 (t, J=5.20 Hz, 2H), 4.20 (t, J=5.20 Hz, 2H), 6.80-6.84 (m, 3H), 7.83 (d, J=8.40 Hz, 2H), 8.07 (d, J=8.00 Hz, 2H). LCMS: RT 1.79 min. LCMS (ES-API), m/z 419.0 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8](C(O)=O)[NH:9]2)=[CH:5][CH:4]=1>N1C2C(=CC=CC=2)C=CC=1>[CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc2cc(C(=O)O)[nH]c2c1
Solvent: c1ccc2ncccc2c1
Product: CSc1ccc2cc[nH]c2c1
Temperature: 215 °C
Yield: 90.6 %

Procedure:
A mixture of 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 46 mmol), Cu powder (2.1 g, 33 mmol) and quinoline (100 ml) was heated at 215° C. for 3 hours. The mixture was cooled to room temperature, filtered through celite, and the filtrate diluted with H2O (500 mL). The cooled mixture was acidified with concentrated HCl (pH=1), and extracted with EtOAc. The organic fraction was washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give of 6-Methylsulfanyl-1H-indole (6.8 g, 90%) after purification by flash column chromatography.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[CH:11]([O-:13])=[O:12].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:13][CH:11]=[O:12]
Reactant: O=C[O-]
Reactant: O=c1oc(CBr)c(CBr)o1
Agent: [K+]
Solvent: CC#N
Product: O=COCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (150 mg, 0.55 mmol) was dissolved in acetonitrile (4.0 mL). Potassium formate (46 mg, 0.55 mmol) was added thereto. This mixture was stirred at 25° C. for 5 hours. Through the ordinary post-treatment, crude Compound S-30 (85 mg, yield 65%) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O>[CH3:1][CH:2]1[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:25][C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: CC1Oc2cc3nc(S)[nH]c3cc2O1
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)OC(C)O4)nc1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 3.9 g of 2-methyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 60 ml of alcohol, were added dropwise while stirring 1.57 g of sodium hydroxide in 30 ml of water and, after 30 minutes, there were added 3.44 g of 5-methyl-2-chloromethylpyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/petroleum ether (low boiling) and there were obtained 4.8 g (81.7% of theory) of 2-methyl-6-[[(5-methyl-2-pyridyl)methyl]-thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 147°-148° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.C(#N)C.Cl.[CH3:23][O:24][NH2:25].C(N(CC)CC)C>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][O:24][CH3:23])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CONc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Reaction time: 3.5 h
Yield: 19.3 %

Procedure:
To a mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), 10 ml of acetonitrile and 334 mg of methoxyamine hydrochloride was added dropwise 506 mg of triethylamine at room temperature to obtain a mixture. The mixture was charged in a pressure-resistant reaction vessel made of stainless steel and the reaction was carried out at 105° C. for 3.5 hours. After cooling, the reaction solution was poured into 100 ml of water. The mixture was extracted with ethyl acetate and the resultant extract was washed with water and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 156 mg of crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain 55 mg of the titled compound. Mp.173.9° C. 1H NMR (CDCl3): 3.98 (3H, s), 7.47-7.72 (6H, m), 7.87 (1H, d, J=9.0 Hz), 7.89 (1H, d, J=2.2 Hz), 8.03 (1H, br. s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:21])[C:11]2[C:16]([CH2:17][CH2:18]/1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2>CCO.[Pt]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21]
Reactant: COc1ccc2c(c1)CC/C(=C\c1ccncc1Br)C2=O
Agent: [Pt]
Solvent: CCO
Product: COc1ccc2c(c1)CCC(Cc1ccncc1Br)C2=O
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Pt/C (5 wt % loading, 200 mg) was added to a stirred solution of the compound 87 (2.0 g, 5.81 mmol) in EtOH (58 mL) at room temperature. The resulting suspension was stirred for 4 hours under H2 atmosphere (1 atm) then filtered over Celite, rinsed with dichloromethane and concentrated to dryness. The crude residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the title compound 99 (Yield 2.0 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: ClCCCBr
Reactant: Sc1cccc(Cl)c1
Product: ClCCCSc1cccc(Cl)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:8]=[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: BrC=C(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 81 %

Procedure:
Into a reactor were introduced 110 g (0.60 mol) of the 1,1-diphenylethylene and 1,098 g of carbon tetrachloride under a nitrogen atmosphere. A solution prepared by mixing 95.9 g (0.60 mol) of bromine with 288 g of carbon tetrachloride was added dropwise thereto over 1 hour with cooling with ice. After completion of the addition, the reaction mixture was stirred at that temperature for 7 hours and then concentrated. To the residue were added 119 g of pyridine and 500 mL of toluene. This mixture was refluxed for 3 hours. After being cooled, the reaction mixture was washed with 5% hydrochloric acid and water, subsequently dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant concentrate was distilled and then recrystallized from methanol to obtain 126 g (81%) of the target compound as white crystals.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[C@@H:32]([CH3:34])[CH2:33][C@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([F:14])[F:15])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1N
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-4-nitro-benzamide was prepared from 2-Amino-N-methyl-4-nitro-benzamide and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1223b. Product was isolated as an orange solid (711 mg, 81%) MP 241 (dec), LCMS 344.10, HPLC purity 80%, 1H-NMR (CDCl3, 400 MHz) δ: 11.72 s, 1H), 9.73 (s, 1H), 8.33 (s, 1H), 7.98 (8.6 Hz, 1H), 7.69 (8.5 Hz, 1H), 6.37 (m, 1H), 3.11 (d, J=4.8 Hz, 3H).