Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].BrCC1C=C(OC)C=CC=1C1C=CC(Cl)=CC=1>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=2[CH3:15])=[CH:20][CH:19]=1)#[N:17]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1ccc(C#N)cc1
Yield: 83.8 %

Procedure:
(Step 1) A solution of tert butyl 4-bromo-3-methylbenzoate (3.3 g, 12.2 mmol) was reacted with 4-cyanophenylboronic acid (2.15 g, 14.6 mmol) according to the procedure described for compound 14. The crude product was purified by column chromatography (silica gel, 3:2 hexanes/methylene dichloride) to afford tert-butyl 4′-cyano-2-methyl-1,1′-biphenyl-4-carboxylate as a white solid (3.0 g, 84% yield). ESI-MS m/e 294.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].Cl[C:11]([C@:13]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:45])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:11]([C@:13]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]2)[C@@:27]2([CH3:32])[C@@H:18]([C@:19]3([CH3:45])[C@@H:24]([CH2:25][CH2:26]2)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:12]
Reactant: COC(=O)CNCCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(2-aminoethylamino)acetate (33.5 mg, 0.254 mmol), Hunig'sBase (0.089 mL, 0.507 mmol) and DMAP (20.66 mg, 0.169 mmol) in DCM (1.5 mL) was added methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (100 mg, 0.169 mmol) in DCM (1.5 mL). The reaction mixture was stirred at 20° C. for three hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (90 mg, 76%). LCMS: m/e 713.45 (M−H)−, 2.75 min (method 1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([OH:17])=O)(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([N:37]([O:38][CH3:39])[CH3:36])=[O:17])(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)Nc1c(C(=O)O)[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1[nH]c2cc(Cl)ccc2c1NC(C)=O
Reaction time: 1 h
Yield: 20 %

Procedure:
To a mixture of (3-acetylamino-6-chloroindole)-2-carboxylic acid (step 3; 280 mg, 1.11 mmol), diphenyl phosphoryl azide (365 mg, 1.33 mmol) and N,O-dimethylhydroxylamine hydrochloride (162 mg, 1.66 mmol) in dimethylformamide (5 ml) was added triethylamine (0.58 ml, 4.16 mmol). After stirring for 1 h, the mixture was poured into water (10 ml) and extracted with diethyl ether (30 ml×2). The combined organic extracts were washed consecutively with water (20 ml×2), saturated sodium bicarbonate (20 ml), brine (20 ml), then dried (MgSO4). Removal of solvent gave the title compound as a brown solid (ca. 20%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH2:30])[N:27]=[CH:13][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Yield: 88.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluorophenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[OH:9][CH:10]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[O:25][CH3:26])[C:11](=[NH:15])[O:12]CC.[O:27]1CCC[CH2:28]1>C1(C)C=CC=CC=1>[CH3:26][O:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH:10]1[O:9][C:28](=[O:27])[NH:12][C:11]1=[O:15]
Reactant: CCOC(=N)C(O)c1c(OC)cccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc([N+](=O)[O-])c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 27, but using 3 rather than 3.2 equivalents of triethylamine, ethyl 1-hydroxy-1-(2-methoxy-6-nitrophenyl)methanecarboximidate hydrochloride (12 g., 0.041 moles) in 400 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-methoxy-6-nitrophenyl)oxazolidine-2,4-dione (8.8 g., 86%; m.p. 181°-183° C.; m/e 252)
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>O.C(O)C>[N+:2](=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])=[N-:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A mixture of sodium azide (683 mg, 10.5 mmol), p-toluenesulfonyl chloride (2.0 grams, 10.5 mmol), and 70% aqueous ethanol (30 mL) was stirred at room temperature for 1 hour. Diethyl malonate (1.62 mL, 10.0 mmol) and triethylamine (1.46 mL, 10.5 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether. The extracts were combined and decanted from the solid that formed. The petroleum ether solution was washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 1.65 grams of diethyl 2-diazomalonate as a yellow oil. IR (KBr): 2138, 1757, 1735, 1320, 1092 cm-1. Decomposition temperature: 175° C. (by DSC).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:32]=[C:33]([CH2:35][O:36][C:37]5[CH:46]=[CH:45][C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[N:38]=5)[N:34]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(OCc3cn4c(-c5ccc(N6CCNCC6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 47a (144 mg, 0.240 mmol) in DCM (1 mL) was added TFA (0.8 mL). The resulting mixture was stirred at rt for 1 h and concentrated under reduced pressure. The residue obtained was dried under reduced pressure overnight, suspended in 20 mL of diethyl ether, sonicated for 5 min and concentrated. The solid obtained was dried under reduced pressure for 4 h to obtain a residue which was dissolved in 1:1 MeOH/DCM solution (5 mL) and filtered through a sodium bicarbonate cartridge. The filtrate was concentrated under reduced pressure and the resulting residue was triturated in ether to give compound 47b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C29H30N8O2: 523.2 (M+H). Found 523.3.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([OH:18])=O)[C:7]1=[O:19])=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:18])[C:7]1=[O:19])=[O:2]
Reactant: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=COCCn1c(=O)c(C(=O)Nc2nnn[nH]2)nc2ccccc21

Procedure:
4(2-Formyloxyethyl)-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid (1 g) and N,N'-carbonyldiimidazole (0.6 g) in dry tetrahydrofuran (100 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the mixture was heated under reflux for 1 hour. The solid was collected and treated with aqueous hydrochloric acid (25 ml., 2N). It was filtered off, dried and crystallised from aqueous dimethylformamide. It had m.p. 240°-241° (d).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([NH2:27])[CH:26]=1)=[O:21].[Br:28]N1C(=O)CCC1=O.O>O1CCCC1>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20]([C:22]1[S:23][C:24]([Br:28])=[C:25]([NH2:27])[CH:26]=1)=[O:21]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)c(Br)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (360 mg, 0.87 mmol) (Example I3) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (NBS) (155 mg, 0.87 mmol). The mixture was stirred at room temperature for 1.5 hours. Water (50 ml) was added and the organic phase was extracted twice with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane) to give 5-bromo-4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (343 mg; 80% yield); 1H-NMR (CDCl3, 400 MHz): 7.26 (s, 2H), 7.10 (s, 1H), 3.8 (s, 2H), 2.24 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2cc(NCc3ccccc3)nc(N)n2)cc1
Temperature: 130 °C
Yield: 40.5 %

Procedure:
0.30 g (0.001 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide and 11 ml (0.1 mol) of benzylamine were dissolved in 15 ml of ethanol and stirred in an autoclave at 130° C. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.15 g (41%) of 4-amino-N-(2-amino-6-benzylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.; 221° C. (dec.).
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>O1CCCC1>[N+:31]([C:30]1[C:25]([C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:1][CH3:2])=[N:26][CH:27]=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(C(=O)OCC)c1ncccc1[N+](=O)[O-]

Procedure:
Diethyl ethylmalonate is dissolved in tetrahydrofuran and treated with one equivalent of sodium bis(trimethylsilyl)amide followed by 2-chloro-3-nitropyridine to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.N1C2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16])=[CH:12][CH:13]=2)[CH:8]=C1.CI.[H-].[Na+]>O>[CH3:1][N:2]1[C:5]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:3]1
Reactant: CC(CCCCOC(=O)c1ccc2[nH]ccc2c1)=C(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2c(ccn2C)c1)=C(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.4 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-5-carboxylate and 0.40 g (2.8 mmol) of methyl iodide, followed by the addition of 0.07 g (1.7 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.36 g (yield: 86%) of 6,6-difluoro-5-methyl-5-hexenyl 1-methyl-1H-indole-5-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C-:17]#[N:18].[Na+]>C(O)C.O>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:17]#[N:18]
Reactant: Fc1cccc(Oc2ccccc2CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1Oc1cccc(F)c1

Procedure:
1-(Chloromethyl)-2-(3-fluorophenoxy)benzene (26.5 g.) was dissolved in 300 ml of ethanol; a solution of sodium cyanide (7.8 g.) in 15 ml of water was added, and the resulting mixture was heated to reflux overnight. The ethanol was evaporated, the residue taken up in water, extracted with ether and the combined ether extracts were dried and concentrated to give the title compound. ##STR13##
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[H][H].[CH3:38]O>O1CCOCC1.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:38])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C

Procedure:
48.6 g of Z-Asp(OtBu)-Phe-OCH 3 in 700 ml of methanol are decarbobenzoxylated in a duck-shaped flask at room temperature after adding 33.5 ml of 3 N hydrogen chloride in dioxane and 5 g of 10% strength palladium catalyst on charcoal. After the hydrogen uptake has ended the mixture is filtered and the filtrate evaporated. 38.7 g of a white foam are obtained. In a thin layer chromatogram on silica gel in chloroform-methanol (9:1) Rf = 0.60; in chloroform-acetone (1:1) Rf = 0.58; Rf102E = 0.42. The product is employed for the subsequent condensation without additional purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[C:15]1(O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[C:23]1([O:1][CH2:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)C1
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A solution of 1.0 g (4.9 mmol) of 1,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (described in WO 0066557), 0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene and 20 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowed to return to ambient temperature and stirring is continued for 24 hours. The mixture is filtered and the precipitate is rinsed with toluene. It is evaporated to dryness. The residue is taken up in dichloromethane and washed with a 1M aqueous sodium hydroxide solution. It is dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 98/2 mixture of dichloromethane and methanol, to give 0.80 g of product in colorless oil form.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8]O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:36])C(=O)C1>C(Cl)Cl>[Cl:36][CH2:8][C@H:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C[C@@H](O)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H](O)CCl
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of (R)-methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and slowly added NCS (124.2 g, 0.93 mol) under ice water cooling. The mixture was stirred at 5° C. for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient) to give (R)methyl 4-chloro-3-hydroxybutanoate (33 g, 26% over 3 steps). 1H NMR (300 MHz, CDCl3)δ 4.18-4.25 (m, 1H), 3.68 (s, 3H), 3.55-3.60 (m, 2H), 3.32-3.33 (d, J=42 Hz, 1H), 2.52-2.68 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1>CN(C=O)C>[ClH:9].[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(C)CCO
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncccc1C#N
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-dimethylaminoethanol (1.3 g, o., 015 m) in DMF (25 mL) was added 57% NaH in mineral oil (0.63 g, 0.015 m). After stirring 0.5 hours at 25° C., a solution of 2-chloro-3-cyanopyridine (2 g, 0.015 m) in DMF (10 mL) was added. The reaction mixture was stirred 20 hours, concentrated to 10 mL and added to H2O (25 mL). The solution was extracted with CHCl3 ; the organic layer was dried, filtered and concentrated. The resulting oil was dissolved in Et2O and treated with HCl in MeOH to yield after recrystallization from Et2O-iso-PrOH 0.8 g (23%) of (XI) m.p. 148°-150° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.[C:12](Cl)(Cl)=[S:13].C(=O)(O)[O-].[Na+]>O.ClCCl>[N:2]([C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[C:12]=[S:13]
Reactant: COC(=O)c1cscc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cscc1N=C=S
Reaction time: 1 h

Procedure:
19.4 g of methyl 4-aminothiophen-3-carboxylate hydrochloride were added to a suspension of 7.7 ml of thiophosgene and 18.5 g of sodium bicarbonate in 70 ml of water and 200 ml of dichloromethane at room temperature in the course of 30 minutes, and stirring was carried out for 1 hour at room temperature. After separation of the phases, the aqueous phase was extracted once with dichloromethane and the combined organic phases were washed once with water, dried over sodium sulfate and evaporated down.