Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH2:45](N)[CH3:46].NC1C=CC=CC=1>>[CH:6]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:8]([CH2:45][CH2:46]1)[CH2:9][O:12][CH2:5]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CCN
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCNC(=O)Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC)c3n2)cc1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing ethylamine (2M in THF) as the aniline component. (46%, MS=422.4 (M+H))
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:8]([C:12]([O:14]C)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[C:16]([C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]2[C:5]([C:6]=1[OH:20])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Temperature: 60 °C
Yield: 94.5 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 3.38 mmol) in water (20 mL) was added an aqueous solution of sodium hydroxide (0.27 g, 6.75 mmol). Upon addition, the suspension dissolved. The reaction mixture was warmed to 60° C. for 1 hour. After this time the reaction was cooled to room temperature and acidified with concentrated hydrochloric acid. The product was then extracted into diethyl ether and ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as a solid (900 mg). This material was purified by recrystallization employing an ethyl acetate/hexane co-solvent system to provide the title compound (571 mg, 60%) as a white solid mp 296° C. (dec); MS (CI)=238 (M+H). Analysis for C12H8NO5Cl.0.45 CH3CO2CH2CH3.0.10 H2O: Calc'd: C, 51.30; H, 3.68; N 4.34, Found: C, 51.28; H, 3.62; N 3.97 1H NMR 8.22 (d, J=8.7 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.7, 1.8 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([NH2:7])=[O:6].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([N:7]=[C:16]=[O:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-fluoro-4-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.025 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[C:3]([C:10]([O:12]CC2C=CC=CC=2)=O)[CH:2]=1.[NH3:20]>>[C:10]([C:3]1[CH:2]=[N:1][CH:6]=[C:5]([CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:12])[NH2:20]
Reactant: O=C([O-])c1cncc(C(=O)OCc2ccccc2)c1
Reactant: N
Product: NC(=O)c1cncc(C(=O)O)c1

Procedure:
Monobenzyl pyridine-3,5-dicarboxylate (compound G2) (1.92 g, 7.5 mmol) is heated in aqueous concentrated ammonia solution (40 mL, 25%) to 90° C. for 6 h. After cooling, the solution is evaporated and the residue is used as crude product without further purification.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:25])=[C:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.Cl>CO.C([O-])([O-])=O.[K+].[K+].O>[OH:4][C:5]1[C:10]2[C:11]([CH3:25])=[C:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1cccc2oc(C(=O)OCc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)OCc2ccc(Cl)cc2)oc2cccc(O)c12
Reaction time: 8 h
Yield: 96 %

Procedure:
To the compound of Example 124 (0.2 g, 0.55 mmoles) dissolved in MeOH (10 ml) was added 2-3 drops K2CO3 10% w/v in H2O and the reaction mixture was stirred at 25° overnight. HCl (0.1N, 20 ml) was added and the mixture was filtered. The solid was air dried to give 0.170 g or 96% of the title compound, m.p. 202°-204° C.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2cc(F)c(F)cc2C1=O
Reaction time: 0.67 h
Yield: 76 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.3 g of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone in 125 ml of anhydrous dichloromethane and 25 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 60 ml of dichoromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 80 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 40 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There was obtained a yellow oil which was crystallized from diethyl ether/hexane. 3.82 g (76%) of (RS)-2-(2-oxoethyl)-5,6-difluoro-1-indanone were obtained as a white solid with m.p. 78°-81°.
Reaction SMILES: P([O-])([O-])([O-])=O.C1C[O:9]CC1.C(#N)C.[N+](C1C=CC(COC(C2N3[C@H](SC=2)C([CH:33]([O:43][C:44](=O)[CH3:45])[C:34]2[CH:42]=[C:41]4[N:36]([CH2:37][S:38][CH2:39][CH2:40]4)[N:35]=2)(Br)C3=O)=O)=CC=1)([O-])=O>[Zn].C(OCC)(=O)C>[CH2:44]([O:43][C:33]([C:34]1[CH:42]=[C:41]2[N:36]([CH2:37][S:38][CH2:39][CH2:40]2)[N:35]=1)=[O:9])[CH3:45]
Reactant: CC(=O)OC(c1cc2n(n1)CSCC2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: C1CCOC1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CSCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
Freshly activated Zn dust (21.4 g) was added rapidly with 0.5 mol/L phosphate buffer (pH 6.5, 112 mL) to the THF (76 mL) and acetonitrile (36 mL) solution of crude (5R)-6-[acetoxy-(4,5-dihydro-6-thia-1,7a-diazainden-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution was cooled at 0° C., and then the pH was adjusted to 8.0. Ethyl acetate (56 mL) was added to the mixture and filtered through a pad of Celite. The pad was washed with water (150 mL). The aqueous layer was separated and then the organic layer was extracted with 0.5 mol/L phosphate buffer (pH 6.5, 2×30 mL). The combined aqueous layers were cooled at 0° C., and then the pH was adjusted to 8.0. The mixture was concentrated to 236 g, and then applied to Diaion HP-21 resin (480 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water (960 mL) and then acetonitrile aqueous solution (5%; 960 mL, 10%; 960 mL, 20%; 960 mL). The combined active fractions were concentrated under high vacuum at 35° C. and lyophilized to give the titled compound as a yellow amorphous solid (1.28 g, 40.5%, pH 7.45).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]3[CH2:26][CH2:27][O:23][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOC2)cn1
Yield: 68 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (120 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=360.4 [M+H]+.
Reaction SMILES: N1[CH2:12][CH2:11]NCCNCCNCC1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:13][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:11][CH3:12]
Reactant: c1ccccc1
Reactant: C1CNCCNCCNCCN1
Product: CCCCCCCCCCCCC

Procedure:
reacting 1,4,7,10 tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10 tetraazatricyclo(5.5.1.0)tridecane,
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])[CH2:37]3)(=[O:33])=[O:32])=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][S:31]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][C:38](=[O:43])/[C:37]/3=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])(=[O:33])=[O:32])=[CH:28][CH:29]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccc(F)cc4)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 74.8 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(4-fluorobenzyl sulfonyl)-2-oxoindolin-3-ylidene)methyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 67 (84 mg, yield 76%) as an orange solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[CH:20]2[Si:25]([CH:28]1[C:36]2[C:31](=[C:32](Br)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH3:38])([CH3:27])[CH3:26]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[CH:20]2[Si:25]([CH:28]1[C:36]2[C:31](=[C:32]([C:11]3[S:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:14][C:13]=4[CH:12]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH3:38])([CH3:27])[CH3:26]
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: c1ccc2sccc2c1
Reactant: [Li]CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3cc4ccccc4s3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3cc4ccccc4s3)cccc21
Reaction time: 2 h

Procedure:
In an argon atmosphere, to a solution of 1.74 g (13.0 mmol) of benzothiophene in 30 ml of THF, 5.24 ml of 2.5 M nBuLi (13.0 mmol) in hexanes was added at ambient temperature. This mixture was stirred for 2 hours, and, then, 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF was added. The resulting mixture was stirred for 1 hour. Then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.37 g (5.0 mmol) of 1 were added. This mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.76 g (95%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:25]Br>CO>[Br:25][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A stirred solution of 3α-hydroxy-5β-pregnane-11,20-dione (10 g.) in dry methanol (700 ml.) was treated at 0° with a solution of bromine (1.9 ml.) in methanol (45 ml.) at such a rate that the yellow colour disappeared before further addition. The solution was then partitioned between water and chloroform. The organic layer was washed with water, dried (Na2SO4) and evaporated. Chromatography of the residue (with benzene/ethyl acetate, 2.5:1) gave title compound (7.2 g.) as a white foam; [α]D + 100°(c 1.1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:13](C)=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.ClC1N=CC=C2C(=O)C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)=C(C3C=CC=CC=3)OC=12.CN1C(C)=C(B2OC(C)(C)C(C)(C)O2)C=N1>>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[C:2](=[O:1])[C:3]([C:26]4[CH:27]=[CH:28][C:29]([C:32]5([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][CH2:33]5)=[CH:30][CH:31]=4)=[C:4]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:5][C:6]=23)[CH:13]=[N:14]1
Reactant: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: Cc1c(-c2nccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 82 %

Procedure:
Following the procedure used to prepare tert-butyl (1-(4-(4-oxo-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate, tert-butyl (1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate was reacted with 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the title compound (46 mg, 82%). LCMS (Method I): RT=7.35 min, [M+H]+=563.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Br:17]Br>C(Cl)Cl>[Br:17][CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[C:13]1=[O:16]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(Br)CC2
Yield: 107.4 %

Procedure:
To a solution of 1.4 g (0.00585 mol) of 7-methanesulfonamido-1-tetralone in 20 mL of methylene chloride was added dropwise a solution of 0.94 g (0.0059 mol) of bromine in 5 mL of methylene chloride. The progress of the reaction was followed by thin layer chromatography (fl. silica gel/CH2Cl2). A few additional drops of the bromine solution were added to completely consume the starting material. The solution was evaporated to dryness to give 2.0 g of 2-bromo-7-methanesulfonamido-1-tetralone, mp 87°-92° C.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]([OH:25])([C:11]1[CH:16]=[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])[N:14]=[C:13]([O:21][CH3:22])[C:12]=1[CH2:23][OH:24])[CH2:9][CH3:10])(C)(C)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH2:9]([C:8]1([OH:25])[C:11]2[C:12](=[C:13]([O:21][CH3:22])[N:14]=[C:15]([Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=2)[CH2:23][O:24][C:6](=[O:5])[CH2:7]1)[CH3:10]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc([Si](C)(C)C)nc(OC)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CC(=O)OCc2c1cc([Si](C)(C)C)nc2OC
Reaction time: 24 h
Yield: 81.6 %

Procedure:
To a 100 mL flask was added the beta hydroxy ester (6) (0.75 g, 1.9 mmol) followed by trifluoroacetic acid (150 mL). After 24 hours, the mixture was poured into sat. NaHCO3 (pH 8) and extracted with ether (3×100 mL). The organic phase was dried (MgSO4) and chromatographed (hexanes:EtOAc 2:1) to give beta-hydroxy lactone (7) 0.48 g (79%) as a white solid: IR (CHCl3, cm−1) 3020, 2978, 2873, 1742, 1561, 1448, 1384, 1348, 1110, 909, 842; 1H NMR (300 MHz, CDCl3) δ0.22 (s, 9H, 0.83 (t, J=7 Hz, 3H, 1.81-1.88 (m, J=7 Hz, 2H, 1.37 (br s, 1H, 3.00 (d, J=14 Hz, 1H, 3.32 (d, J=14 Hz, 1H, 3.91 (s, 3H, 5.18.(d, J=15 Hz, 1H, 5.42 (d, J=15 Hz, 1H, 7.26 (s, 1H; 13C NMR (75 MHz, CDCl3) δ−1.9, 8.4, 33.9, 42.9, 53.8, 62.2, 73.8, 114.7, 121.2, 151.6, 159.8, 165.9, 172.3; HRMS (EI) m/z calcd for C15H23NO4Si (M+) 309.1396, found 309.1399 LRMS (EI) m/z 309 (M+), 294, 266, 252, 238, 89.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CCCC)CCCC)CCC.Cl[CH2:20][C:21](Cl)=[O:22].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>CN(C=O)C.C(O)(C)C>[CH2:24]([N:27]1[CH2:20][C:21](=[O:22])[C:2]([C:3]#[N:4])=[C:1]1[NH2:5])[CH:25]=[CH2:26]
Reactant: O=C(Cl)CCl
Reactant: C=CCN
Reactant: N#CCC#N
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C=CCN1CC(=O)C(C#N)=C1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.8 g of malononitrile were dissolved in 30 ml of DMF and cooled to 0° C. While cooling, 87 g of tributylamine and 27 g of chloroacetyl chloride were simultaneously added dropwise to this, and the mixture was stirred at 10° C. for 10 minutes. The mixture was then added to a mixture of 300 g of ice and 43 g of allylamine and stirred at room temperature for 8 hours. The precipitate was filtered off with suction, washed and dried. 38.1 g (78% of theory) of impure crude product were obtained and were boiled in 150 ml of isopropanol to purify. After cooling to 5° C., the precipitate was filtered off with suction, washed and dried. 31.2 g (64% of theory) of the compound of the formula ##STR26## of melting point 275° to 278° C. were obtained The IR, NMR, UV and mass spectra and the elemental analysis are consistent with the structural formula.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1.C(Cl)Cl>O1CCOCC1.O.O>[N:1]1([C:10]2[N:15]=[C:14]([N:28]3[CH2:27][C@@H:26]([CH3:25])[O:31][C@@H:30]([CH3:32])[CH2:29]3)[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1cc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(c2cc(N3CCOCC3)nc(-n3cnc4ccccc43)n2)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To the obtained 2-(benzimidazol-1-yl)-4-chloro-6-morpholinopyrimidine (318 mg, 1.00 mmol) dissolved in dioxane—water solution (4:1), sodium hydroxide (100 mg, 4.3 mmol) and cis-2,6-dimethylmorpholine (126 mg, 1.20 mmol) were added and stirred at 80° C. for 12 hours. The reaction mixture was condensed under reduced pressure and the obtained residue was mixed with methylene chloride and water and shaken. Organic layer was separated from the mixture and washed with water and dried over anhydrous magnesium sulfate. The solvent was removed out under reduced pressure and the residue was purified by silica gel column chromatography to obtain 340 mg of the titled compound (yield: 86%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH2:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=O
Reactant: CCCCCCNCCCCCC
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCN(CCCCCC)CON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 18.54 g of di-n-hexylamine, to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)[N:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(O)=O.CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([CH2:17][N:27]4[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]4)[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CN(C)C1CCN(Cc2cccc(Nc3nccc(-c4ccc(Br)s4)n3)c2)CC1
Yield: 7.1 %

Procedure:
A solution of 3-[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzaldehyde (25 mg, 0.069 mmol) and 4-dimethylaminopiperidine (13.3 mg, 0.104 mmol) in 25% HOAc in DMA was mixed for 2 h and then treated with MP-CNBH3 (2.5 eq.) for 18 h. The reactions were filtered and purified directly by LCMS to afford title compound (2.3 mg, 7%) for 2 steps. MS: m/z 472 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ1.37 (br q, J=11 Hz, 2H), 1.70 (br d, J=12 Hz, 2H), 1.94 (br t, J=11 Hz, 2H), 2.04 (br t, 1H), 2.87 (br d, J=11 Hz, 2H), 3.33 (s, 2H), 6.89 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.33 (dd, J=1, 5 Hz, 1H), 7.37 (m, 1H), 7.55 (br d, J=8 Hz, 1H), 7.86 (m, 1H), 7.89 (br s, 1H), 8.51 (dd, J=1.5, 5 Hz, 1H), 9.68 (s, 1H).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:26])[F:25])[C:16](=[O:29])[C:15]([C:30]([O:32]CC)=[O:31])=[CH:14]2)[CH2:12][CH2:11]1>O>[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:25])[F:26])[C:16](=[O:29])[C:15]([C:30]([OH:32])=[O:31])=[CH:14]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water were added to 1.40 g (0.0039 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX), R1 =--OCHF2, R3' =H, R17 =C2H5, X=F] (prepared as described in Preparation 6), and the mixture was heated under reflux for 1 hour. At the end of this time, it was cooled to room temperature and poured into ice-water. The precipitated crystals were collected by filtration and washed with water and with diethyl ether, in that order, to give 1.09 g of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles, melting at 202°-207° C.