Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:25])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:18]([Cl:23])[C:17]=3[Cl:24])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(Br)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(4-(3-(5-(4-bromophenyl)thien-2-yl)-3-oxopropyl)-2,3-dichlorophenoxy)-2-methylpropanoate is prepared from 1-(5-(4-bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)propan-1-one according to general procedure D, using 4 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C[O:23][C:24]1[CH:33]=[C:32]2[C:27](CCC[CH:31]2[NH2:34])=CC=1.[CH2:35]([N:38]([CH2:52][CH2:53][CH3:54])[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([CH2:50]C)[CH:49]=1)C(O)=O)=[O:40])[CH2:36][CH3:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[C:43]1[CH:47]=[C:48]([CH3:50])[CH:49]=[C:41]([C:39]([N:38]([CH2:35][CH2:36][CH3:37])[CH2:52][CH2:53][CH3:54])=[O:40])[CH:42]=1)[C@H:11]([OH:12])[CH2:13][NH:34][CH2:31][C:32]1[CH:33]=[CH:24][O:23][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: COc1ccc2c(c1)C(N)CCC2
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2ccoc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3), 3-furylmethylamine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=542.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:28][CH2:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[CH2:27][CH2:28]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) in ethanol (20 mL) were added tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) and Et3N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to give the product as a light yellow solid (387.1 mg, 34.5%).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[C:6]1([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[CH2:20]([NH2:22])[CH3:21]>O>[CH2:20]([NH:22][S:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:5])=[O:3])[CH3:21]
Reactant: CCN
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCNS(=O)(=O)c1ccccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
A 1 liter flask equipped as in Example 2 was charged with 254 gms (2.18 moles) of chlorosulfonic acid, and then 100 gms (0.62 moles) of phenylcyclohexane was added to the stirred chlorosulfonic acid over a 11/2 hour period at 25° C. to 30° C. under N2. The mixture was stirred at 25° C. under N2 for 4 hours and then it was added to a mixture of 376 gms of 50 percent sodium hydroxide (4.7 moles), 500 mls of deionized water and 40 gms (0.62 moles) of 70 percent ethylamine at 40° C. to 50° C. over a 2 hour period at a pH above 10. The cooled reaction mixture was filtered to isolate a tan solid which was then washed with water and recrystallized from cyclohexane to give 48.7 gms (28.9% yield), m.p. 100°-101.5° C., proton NMR consistent with N-ethyl cyclohexylbenzene sulfonamide structure.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1S.O>C1COCC1>[CH2:19]([CH:3]([CH2:1][CH3:2])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[S:13][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[CH:9][CH:10]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH3:20]
Reactant: Nc1ccccc1S
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1cncn1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)C(c1ccc(Nc2nc3ccccc3s2)cc1)n1cncn1
Yield: 49.6 %

Procedure:
A mixture of intermediate (19b) (0.1665 mol) and 2-aminobenzenethiol (0.2 mol) in THF (500 ml) was stirred and refluxed overnight. The mixture was cooled, poured out into water, extracted with CH2Cl2 and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 97.5/2.5/0.1. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone/diethyl ether. The precipitate was filtered off and dried, yielding 31.2 g (49.6%) of (±)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (comp. 25).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][CH:8]2[N:4]([C:5](=[O:19])[C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]2)[CH2:3]1.Cl[C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[O:19]=[C:5]1[N:4]2[C@@H:8]([CH2:9][CH2:10][C@H:2]([NH:1][C:21]3[C:22]4[CH:29]=[CH:28][N:27]([S:30]([C:33]5[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=5)(=[O:31])=[O:32])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:3]2)[CH2:7][C@@H:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17].[O:19]=[C:5]1[N:4]2[C@H:8]([CH2:9][CH2:10][C@@H:2]([NH:1][C:21]3[C:22]4[CH:29]=[CH:28][N:27]([S:30]([C:33]5[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=5)(=[O:31])=[O:32])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:3]2)[CH2:7][C@@H:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC2CCC(N)CN2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](NC(=O)OC(C)(C)C)C(=O)N5C4)ncnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H]4CC[C@H]5C[C@H](NC(=O)OC(C)(C)C)C(=O)N5C4)ncnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl(2S)-6-amino-3-oxooctahydroindolizin-2-ylcarbamate 127.2 (0.913 g, 3.39 mmol) in DMF (25 ml) and was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg (3.4 mmole) 127.a and DIEA (1.18 mL (6.78 mmole) at solution was heated 90° C. for 24 hr. After cooling to room temperature, the mixture was diluted with H2O and washed with EtOAc (2×). The combined organics were washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo, absorbing onto 6 g silica gel. Purification by flash column chromatography (ISCO 40 g SiO2, 50% EtOAc/hexanes then gradient to 100% EtOAc/hexanes) yielded 0.52 g of tert-butyl (2S,6S,8aS)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate 127.3 and 0.55 g of tert-butyl (2S,6R,8 aR)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)octahydroindolizin-2-ylcarbamate 127.4.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:27]2[CH2:29][CH2:28]2)[C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)#[N:2].[OH-].[K+].C([OH:36])(C)(C)C>O>[NH2:2][C:1](=[O:36])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH:27]2[CH2:28][CH2:29]2)[C:12](=[O:26])[C:13]2[CH:14]=[CH:15][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)O
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC#N)CC2)C2CC2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC(N)=O)CC2)C2CC2)cc1)C(F)(F)F
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To (S)—N-(4-(2-cyanoethyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above (0.040 g, 0.098 mmol) and KOH (0.55 g, 0.98 mmol) was added tert-butanol (3.75 mL). The mixture was heated to 85° C. and stirred for 15 h. The solution was diluted with water (10 mL) and extracted with 10% MeOH in CH2Cl2 (2×15 mL). The combined organics were dried over Na2SO4 and removed in vacuo. Silica gel chromatography (gradient of 0-10% MeOH in CH2Cl2) afforded (S)—N-(4-(3-amino-3-oxopropyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. 1H NMR (500 MHz, CD3OD): δ 0.45 (bs, 2H), 0.58 (bs, 2H), 1.05-1.15 (m, 2H), 1.27-1.48 (m, 2H), 1.51-1.59 (m, 2H), 1.77 (s, 3H), 1.90-2.00 (m, 5H), 2.25-2.28 (m, 2H), 2.71 (bs, 1H), 4.00 (bs, 1H), 7.52 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:40])=[N-]>CO.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:37][CH3:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
The resulting crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and a solution of diazomethane in ether is added at 0° C. After 10 minutes, the solution is carefully concentrated and the residue is dried under a high vacuum. The residue is purified by thick layer chromatography (toluene/ethyl acetate, 3:1, silica gel). After eluting the silica gel of the zone at Rf=0.17 with ethyl acetate, and concentrating the solution on a rotary evaporator, 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained; melting point 120° C. (from ether).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][CH:2]1[CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH:2]1[O:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1Oc2cccnc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1Oc2cccnc2O1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A solution of intermediate (5) (0.018 mol) and triethyl amine (0.036 mol) in DCM (80 ml) was stirred and cooled with an ice-water bath. Methanesulfonyl chloride (0.027 mol) was added dropwise and the resulting reaction mixture was stirred for one hour while cooling on an ice-bath. The crude reaction mixture was washed with water and brine, then extracted. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 4.2 g of (±)-1,3-dioxolo[4,5-b]pyridine-2-methanol methanesulfonate (ester) (intermediate 6).
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.[CH2:6]([C:8]1[C:9]([C:31](=[O:35])[C:32]([NH-:34])=[O:33])=[C:10]2[N:15]([C:16]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][C:12]([OH:30])=[CH:11]2)[CH3:7].[CH3:36][C:37](C)([O-])C.[K+].O>O1CCCC1>[C:1]([CH2:36][CH2:37][O:30][C:12]1[CH:13]=[CH:14][N:15]2[C:10]([CH:11]=1)=[C:9]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])[C:8]([CH2:6][CH3:7])=[C:16]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:3][CH3:2])=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: CCc1c(C(=O)C([NH-])=O)c2cc(O)ccn2c1Cc1ccccc1-c1ccccc1
Reactant: O=C1CCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCOc1ccn2c(Cc3ccccc3-c3ccccc3)c(CC)c(C(=O)C(N)=O)c2c1
Reaction time: 21 h

Procedure:
Propiolactone (25 mg, 0.336 m mol) was added dropwise to a solution of 65c (133.7 mg, 0.336 m mol) and potassium t-butoxide (37.6 mg, 0.336 m mol) in tetrahydrofuran (4 ml) under nitrogen. The mixture was stirred for 21 hr. Water was added. The mixture was washed with ethyl acetate. The aqueous phase was acidified with hydrochloric acid. The precipitate was collected with filtration to give 70b, 96.2 mg (60.9%). Mp, 99-108° C. (dec.). IR nmax (KBr) 3700-2400, 3182, 2968, 2931, 1719, 1677, 1644 cm−1. 1H NMR (CDCl3) δ 1.19 (3H, t, J=7.5 Hz), 2.80 (2H, t, J=6.3 Hz), 2.92 (2H, q, J=7.5 Hz), 4.08 (2H, s), 4.30 (2H, t, J=6.3 Hz), 6.35 (1H, dd, J=2.7, 7.8 Hz), 6.84 (1H, d, J=7.8 Hz), 7.12-7.53 (9H, m), 7.72 (1H, d, J=2.7 Hz). Analyses: Calc'd for C28H26N2O5.1.2H2O: C, 68.34; H, 5.82; N, 5.69. Found: C, 68.40; H, 5.76; N, 5.43.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.N[C:28]1C=CC=CC=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][C:21]4[CH:22]=[CH:28][CH:24]=[CH:25][CH:26]=4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3cc(CNc4cccnc4)ccc3n2)o1
Reactant: Nc1ccccc1
Product: Cc1ccc(CNc2ccc3cc(CNc4ccccc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=344.3 (M+H+), was prepared in accordance with the general method of example 49 from (5-methyl-furan-2-ylmethyl)-[6-(pyridin-3-ylaminomethyl)-quinolin-2-yl]-amine and aniline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)c2c(-c3ccc(OCC4CO4)cc3)oc3ccccc23)cc1

Procedure:
A mixture of 2.0 g. (6.1 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran, 2.6 g. (0.019 mol.) of epibromohydrin and 3.0 g. (0.021 mol.) of potassium carbonate in 100 ml. of dry acetone was refluxed for 12 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give 2-[4'-(2,3-epoxypropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:11](C)=[CH:10]C(C)=[N:8][N:7]([CH3:14])[C:6]=2[N:15]=1.Cl>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:11]([CH3:10])=[N:8][N:7]([CH3:14])[C:6]=2[N:15]=1
Reactant: CC1=CC(C)=NN(C)c2nc(N)[nH]c(=O)c21
Agent: Cl
Solvent: CO
Product: Cc1nn(C)c2nc(N)[nH]c(=O)c12
Reaction time: 8 h

Procedure:
A mixture of 8-amino-1,3,5-trimethyl-1H-pyrimido-{4,5-c}-1,2-diazepin-6(7H)-one (219 mg) and N hydrochloric acid (3 ml) was heated using a hot water bath (>85° C.) for 2 hours. During that period a solution formed before crystals gradually began to separate. The mixture stood at room temperature overnight before the straw-coloured crystals were collected, washed with water and dried under vacuum (70° C.) to yield 140 mg (78%) of analytically pure product: mp >300°; nmr (DMSO-d6) δ 2.28 (s, 3H), 3.60 (s, 3H), 6.52 (br s, 2H), 10.30 (br s, 1H); uv λ max (CH3OH) 217 nm (ε 26,800), 254 (13,000). Mass spectrum (120° C., 70 ev): M, m/e 179, 100%.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.CO>[CH2:26]([O:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)OC)cc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2cc(OCc3ccccc3)c(C(=O)OC)cc2c1
Temperature: 100 °C
Yield: 68.8 %

Procedure:
2-Hydroxy-3,6-di-methoxycarbonylnaphthalene (2.7 g) obtained in Example 26 was dissolved in N,N-dimethylformamide (50 g), followed by heating to 100° C. Potassium carbonate (1.5 g) was slowly added and benzyl chloride (1.4 g) was added dropwise. After heating for about 20 hours, the reaction solution was poured into a mixed solution of water (300 g) and methanol (100 g). The deposit was filtered and then washed with water to obtain 2.5 g of 2-benzyloxy-3,6-di-methoxycarbonylnaphthalene as whitish yellow powder (DSC analysis value: 113.8° C.).
Reaction SMILES: [O:1]=C(CCC)CP(=O)(OCC)OCC.[H-].[Na+].[C:17]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[CH3:18].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20](/[C:17](/[CH3:18])=[CH:27]/[C:28]([O:29][CH2:30][CH3:26])=[O:1])[CH:21]=1
Reactant: C1CCOC1
Reactant: CCCC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C(\C)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Diethyl 2-oxopentyl-phosphonate (1.85 g, 8.26 mol) was added dropwise to a suspension of sodium hydride (0.50 g, 12.4 mmol, 60%) in dry THF (15 ml) followed by 3-acetyl pyridine (1.00 g, 8.26 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature, quenched with acetic acid and was adjusted to pH-6. The reaction mixture was diluted with water and extracted with CHCl3. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to yield the crude compound. Purification by column chromatography by means of neutral alumina using 10-15% ethyl acetate in petroleum ether as eluent afforded 600 mg (40%) of (E)-ethyl 3-(pyridin-3-yl)but-2-enoate as colorless liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.C[CH2:6][CH:7]([NH:9][CH:10]([CH3:12])[CH3:11])O.C(O)C.[CH:16]([Cl:19])(Cl)Cl>>[ClH:3].[CH3:6][CH:7]([NH:9][CH:10]([CH3:12])[CH3:11])[CH2:16][Cl:19]
Reactant: CCC(O)NC(C)C
Reactant: O=S(Cl)Cl
Reactant: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)NC(C)CCl
Product: Cl

Procedure:
Thionyl chloride (57 ml. 0.775 M) is added with stirring and cooling (below 20°) to a solution of 2-methylisopropylaminoethanol (75 g., 0.64 M) dissolved in chloroform (300 ml.). The temperature is raised to 45° at which point gas evolution becomes evident and is maintained at 45°-55° for 11/2 hour. The reaction mixture is refluxed for 2 hours. Then the mixture is cooled to 25° and ethanol (25 ml.) is added with stirring and the mixture is concentrated under vacuum. The residue is taken up in isopropanol (50 ml.) and ether (350 ml.) is added. The product is filtered and on drying, weights 107 g., melting point 114°-117°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12](CC3C=CC=CC=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[C:14]([CH3:15])=[C:13]([CH3:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(Nc3cccc(Cl)c3)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (2.76 mmol) of 4-(m-chloroanilino)-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine and 2.57 g (19.32 mmol) of AlCl3 are heated at reflux in 20 ml of toluene for 2 hours, until all starting material has disappeared in a TLC. The reaction solution is cooled to RT, poured onto ice-water and stirred at 0° C. for 2 hours. The precipitate is filtered off with suction and dissolved in hot ethyl acetate. The ethyl acetate solution is washed twice each with 5% sodium hydrogen carbonate solution and sat. NaCl solution, is dried and is concentrated by evaporation. The residue is crystallised from ethyl acetate/hexane, yielding 4-(m-chloroanilino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine in the form of colourless crystals having a melting point of 239°-240° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]=O)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>CC#N.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC=O)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCCN2CCN(C)CC2)c1F
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-(4-oxo-butyl)-3H benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11n (15 mg, 0.030 mmol) is dissolved in MeCN (500 μL) and methylpiperazine (10 μl, 0.089 mmol) is added followed by AcOH (5 μL, 0.089 mmol). After 5 minutes, tetramethylammonium triacetoxyborohydride (12 mg, 0.045 mmol) is added. After 5 minutes, the reaction mixture is diluted with ethyl acetate and washed with NaHCO3 and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give 12 mg (69%) of pure desired product as a white solid. MS APCI (−) m/z 587, 585 (M−1 Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.98 (s, 1H), 7.30 (d, 1H), 7.08 (dd, 1H), 6.30 (d, 1H), 6.1 (broad singlet, 1H), 4.26 (t, 2H), 3.64 (d, 2H), 3.37 (s, 1H), 2.45 (broad, 8H), 2.41 (s, 3H), 2.38 (t, 2H), 2.28 (s, 3H), 1.95 (quin, 2H), 1.55 (quin, 2H), 0.98 (m, 1H), 0.50 (qt, 2H), 0.22 (qt, 2H).
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(Cl)(Cl)[Cl:13]>CN(C)C=O>[Cl:13][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1cnc(O)cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 81 %

Procedure:
Methyl 5-hydroxypyrazine-2-carboxylate (673 mg, 4.37 mmol) synthesized in Example (62a) was dissolved in phosphorous oxytrichloride (6.1 mL), and a few drops of N,N-dimethylformamide were added, followed by heating to reflux for 2 hours under nitrogen atmosphere. The reaction solution was poured into ice water, and extraction was carried out three times with chloroform (30 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 mL each), and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (611 mg, yield 81%) as a gray solid.