Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[C:38]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: O=C1CCCC1
Product: COc1cc(C(=O)NC2CN(C3CCCC3)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and cyclopentanone. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.35 (m, 2 H) 1.38-1.78 (m, 11 H) 1.96 (br. s., 2 H) 2.67 (br. s., 1 H) 2.87 (t, J=7.33 Hz, 2 H) 3.49 (t, J=7.33 Hz, 2 H) 3.91 (s, 3 H) 4.08 (t, J=13.77 Hz, 2 H) 4.33-4.44 (m, 1 H) 4.78-4.88 (m, 1 H) 7.19 (d, J=6.57 Hz, 1 H) 8.05 (s, 1 H) 8.25 (d, J=13.39 Hz, 1 H) 8.30 (s, 1 H) 8.41 (dd, J=6.82, 3.03 Hz, 1 H). [M+H] calculated for C29H36F3N7O3, 588; found 588.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:25]1[C:34]2[C:29](=[C:30]([NH:35]N)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1>>[CH:25]1[C:34]2[C:29](=[C:30]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1
Reactant: NNc1cccc2cnccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and isoquinolin-5-yl-hydrazine according to the method described for example 43. MS: M=444.5 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11]>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1I
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1I
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 4-iodo-3-methyl-benzoic acid (5.2 g, 20 mmol) in THF (30 mL), is added 2.0 M borane-dimethyl sulfide complex in THF (40.0 mL, 80 mmol) dropwise. The reaction mixture is stirred overnight. The reaction mixture is quenched carefully at 0° C. with methanol (20 mL) and the mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (80 mL) and water (60 mL). The organic phase is washed with brine (60 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (AnaLogix, gradient EtOAc/Hexane) to give (4-Iodo-3-methyl-phenyl)-methanol as white solid (4.7 g, 95%). 1HNMR (CDCl3) (ppm): 2.4 (3H, s), 4.55 (2H, s), 6.8-7.75 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]([CH3:12])=O>>[CH3:9][C:10]1([CH3:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: CC(C)=O
Reactant: Nc1ccccc1S
Product: CC1(C)Nc2ccccc2S1
Yield: 53 %

Procedure:
Using the method of Example 17a reaction of o-aminothiophenol with acetone yielded 53% of 2,2-dimethylbenzothiazolidine b.p. 120° C./10.2 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 215.8 %

Procedure:
2,4-Difluorobenzoic acid (100 g, 633 mmol) was dissolved in concentrated sulfuric acid (400 ml), and N-iodosuccinimide (142 g, 601 mol) was added by portions at not more than 5° C. After the completion of the addition, the mixture was stirred at the same temperature for 6 hr. The reaction mixture was poured into ice water (ca. 2400 ml), then saturated aqueous sodium sulfite solution was added, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give crude crystals (188 g). The crude crystals obtained in the same manner were combined (total amount 568 g), and recrystallized from 50% aqueous ethanol (2600 ml) to give 2,4-difluoro-5-iodobenzoic acid (388 g, yield 68%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1>C1CCCCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:3]=1
Reactant: N#Cc1cc(C#N)c(Cl)nc1N
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N)c(C#N)c1
Yield: 73 %

Procedure:
2-Amino-3,5-dicyanopyridine (5) was prepared from 3 using the procedure described below for the preparation of 5 except that 5 was recrystallised from MeCN [methyl cyanide; acetonitrile) (instead of EtOH). The yield was 73% (7.00 g from 12.0 g (67.2 mmol) of 3] of product homogeneous on TLC (cyclohexane-EtOAc, 1:1); mp 220° C. dec; 1H NMR (Me2SO-d6) δ7.90 (s, NH2), 8.40 and 8.58 (two d, 4-H and 6H, J=2 Hz).
Reaction SMILES: [Na+].C([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=O)C.[OH-].[Na+].Cl>O>[SH:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9]
Reactant: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(CS)C(=O)Nc2cccc(C(=O)O)c2)cc1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-methoxyphenyl)-propionyl] amino]benzoic acid sodium salt (compound of Example 36) (1.8 g) is dissolved in water (30 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 2.5 with 10% hydrochloric acid. The mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and ethyl acetate is distilled off. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure and the residue is lyophilized to give the title compound (0.6 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O.C(N(CC)CC)C.C(Cl)[Cl:25]>P(Cl)(Cl)(Cl)=O>[Cl:25][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Oc1ncnc2ccc(OC(F)(F)F)cc12
Reactant: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation D4, Step 5: A suspension of 6-(trifluoromethoxy)quinazolin-4-ol (515 mg, 2.23 mmol) in phosphorous oxychloride (1.9 mL) was treated with triethylamine (3 mL, 21.1 mmol), and the mixture was heated at reflux for 2 h. The resulting solution was cooled to room temperature, and stripped 3× from methylene chloride to remove residual phosphorous oxychloride. The residue was dissolved in 100 mL methylene chloride, 100 mL saturated sodium bicarbonate was carefully added, causing vigorous gas evolution, and the mixture was stirred for 10 min, until gas evolution had ceased. The layers were separated, and the organic phase was washed with saturated sodium bicarbonate (2×30 mL), followed by brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% EtOAc/heptane, to yield 377 mg of 4-chloro-6-(trifluoromethoxy)quinazoline as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1 H), 8.16 (d, J=9.23 Hz, 1 H), 8.10 (s, 1 H), 7.83 (dd, J=9.23, 2.20 Hz, 1 H). MS (ES+)=249 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39](C=O)[CH3:40]>C(Cl)Cl.CNC.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)C=O
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(N(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide, (0.054 g, 0.1 mmol) was dissolved in a mixture of DMF (0.5 mL) and CH2Cl2 (10 mL), and 40% dimethylamine in water (1 mL) was added. The mixture was stirred under argon at room temperature for 3 h. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with 10-60% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. The solid was crystallized from CH2Cl2/hexane to give the title compound as a white crystalline solid. mp 214-215° C.; LC-MS m/z 521 (M+H)+, 2.0 min (ret. time).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][NH:67][CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1>CN(C=O)C>[F:56][C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=1[C:64]1[CH2:68][N:67]([C:13]([C@@H:9]([NH2:8])[CH:10]([CH3:12])[CH3:11])=[O:14])[CH:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:65]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 20 h

Procedure:
N-(tert-butoxycarbonyl)-L-valine (101 mg, 0.464 mmol, 2.00 equiv), PYBOP (243 mg, 0.467 mmol, 2.00 equiv), and triethylamine (0.163 mL, 1.17 mmol, 5.00 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24, 0.233 mmol, 1 equiv) in DMF (10 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between a 3:1 mixture of saturated aqueous sodium bicarbonate solution and brine (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 mL), and the resulting solution was allowed to stand for 45 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TPA present) to provide (1S)-1-{[4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2-methylpropylamine (15-1) as a 1:1 mixture of diastereomers (tan gum) (isolated as the TFA salt). LRMS m/z (M+H) 357.2 found, 357.2 required.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:49][N:50]([C@@H:67]([C:75](=[O:86])[N:76]([CH3:85])[CH2:77][CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][N:80]=1)[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:51](=[O:66])[C@H:52]([NH:64][CH3:65])[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:64]([CH3:65])[C@@H:52]([C:51](=[O:66])[N:50]([CH3:49])[C@@H:67]([C:75](=[O:86])[N:76]([CH3:85])[CH2:77][CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][N:80]=1)[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (2.87 g, 11.8 mmol), 1-hydroxy-7-azabenzotriazole (1.6 g, 11.8 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.26 g, 11.8 mmol) were dissolved in dichloromethane (30 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (2.0 mL, 11.8 mmol) was added. (2R)-N-Methyl-2-(methylamino)-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}-3-(2-naphthyl)propionamide (6.0 g, 11.8 mmol) dissolved in dichloromethan (10 mL) was added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 5.28 g of ((3E)-1,1-Dimethyl-4-{N-methyl-N-[(1R)1-(N-methyl-N{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamoyl}but-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1C#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccccc1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (0.768 g, 4.74 mmoles) in dry DMF (10 ml) was added under stirring at room temperature with 60% NaH (189.6 mg, 4.74 mmoles) and the mixture was stirred for 1 hour, then dropwise added with 1-chloro-6-methoxy-5-phenylethynyl-phthalazine (700 mg, 2.37 mmoles), prepared as described in example 61, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 3:7). The separated product was taken up in ethyl ether and crystallised from 30 ml of ethyl acetate/CH2Cl2 to give 600 mg of the title compound (yield: 60%). m.p.: 217-219° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CN(C=O)C.C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:31]([C:27]5[S:26][CH:30]=[CH:29][CH:28]=5)=[O:32])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Reactant: O=C(Cl)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1)c1cccs1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine (100 mg; 0.272 mmol) was dissolved in 3 mL of a mixture (2:1) of dry DMF/THF and stirred under a nitrogen atmosphere at ambient temperature. Sodium hydride (15 mg, 0.375 mmol, 60% oil dispersion) was added To the reaction and stirred for 30 minutes. Thiophenecarbonylchloride (32 μL; 43.7 mg; 0.299 mmol) in 500 μL of dry DMF was added dropwise over 2 minutes and the reaction was stirred for 18 hours at ambient temperature. Workup was affected by removing the solvents under reduced pressure and the resulting residue was triturated with methyltertbutyl ether. The crude solid was purified via silica column chromatography with 5% ethanol in methylenechloride to yield 32 mg of a tan powder; 24% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.2 (s, 1H), 8.92 (s, 1H), 8.88 (d, 1H), 8.39 (d, 1H), 8.35 (s, 1H), 8.3 (d, 1H), 8.23 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.87 (d, 1H), 7.65 (t, 1H), 7.24 (t, 1H) in ppm. LC-MS (ES+) m/e=477/479 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].O[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1.O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:15][CH:16]=1)#[N:19]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: N#Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2ccc(C#N)cc2)cc1
Yield: 43.8 %

Procedure:
Methyl 4-(1-hydroxyethyl)benzoate (540 mg, 3 mmol), 3-hydroxybenzonitrile (360 mg, 3 mmol), triphenylphosphine (1.04 mg, 4 mmol), azodicarboxylic acid diisopropyl ester (800 mg, 4 mmol) in tetrahydrofuran (130 mL) were stirred at 20° C. for 12 hours. Water was added and the mixture was extracted with ethyl acetate (150 mL×3), the combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give methyl 4-(1-(4-cyanophenoxy)ethyl)benzoate (370 mg, 45%) as colorless oil. LRMS (M+H+) m/z: calcd 281.11. found 281.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([O-:26])=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+].[CH2:34](O)[CH3:35]>>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([O:26][CH2:34][CH3:35])=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=C([O-])c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Temperature: 25 °C
Reaction time: 3.8 h

Procedure:
A mixture of ethyl (4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate (0.800 g) and 2.14 g of stannous chloride dihydrate in 36 ml of ethanol is refluxed for 1 hour, cooled to room temperature and diluted with ice water. The mixture is made basic with 10% sodium bicarbonate and stirred 3.8 hours. The mixture is extracted with chloroform and the extracts combined, treated with activated carbon and filtered through anhydrous magnesium sulfate. The filtrate is concentrated under vacuum to give 0.690 g of ethyl 4,5-dihydro-6-(4-aminobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate as a tan foam: mass spectrum (CI) 393 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: OCCCSc1cccc2nccn12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (2.00 g, 9.60 mmoles) and triethylamine (1.60 ml, 11.5 mmoles) in methylene chloride (50 ml) was added acetic anhydride (1.10 ml, 11.6 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 7.5 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:hexane/acetone (1:1)] to obtain 2.40 g of the desired product (100%, brown oily product).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.1 g. of ethyl 4-(5H-dibenzo[a,d]cycloheptene-Δ5,α -acetamido) benzoate, 300 mg. of sodium hydroxide, 8 ml. of water, and 250 ml. of ethanol is refluxed for 4 hours, cooled, diluted with 500 ml. of water, and acidified with concentrated hydrochloric acid. After cooling and stirring for 30 minutes, the solid is collected, washed with water, dried, dissolved in 50 ml. of acetone, and filtered. To the filtrate is added 75 ml. of acetonitrile. The solvent is partially evaporated, and the solid is collected by filtration to yield 1.5 g. of the desired product as a white solid, m.p. 248°-250° C.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[CH:17]=[CH:16][C:15]([I:1])=[CH:14][C:5]=1[CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CNCc1ccccc1N
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CNCc1cc(I)ccc1N
Yield: 73.5 %

Procedure:
Iodine monochloride (3.24 g) was added to a stirred solution of ethyl N-(2-aminobenzyl)glycinate (4.16 g) (see U.S. Pat. No. 3,983,120) and sodium acetate (1.804 g) in acetic acid (100 cm3) at room temperature. After 1 hour volatile material was removed in vacuo and the residue was partitioned between chloroform (200 -cm3) and saturated aqueous sodium carbonate solution (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined organic extracts were washed with 10% aqueous sodium thiosulphate solution (50 cm3). The dried (MgSO4) organic extracts were evaporated in vacuo and the oily residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting witb chloroform. Combination and evaporation of the appropriate fractions gave a solid (4.9 g), a small portion of which was recrystallised from hexane-ethyl acetate to afford the title compound, m.p. 58°-61°.