Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[S:10][C:5]=2[C:4](=[O:16])[NH:3]1.[Br:18]Br.C([O-])(O)=O.[Na+].CC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>C(O)(=O)C.CN(C=O)C>[Br:18][C:8]1[C:6]2[NH:7][C:2]([CH3:17])([CH3:1])[NH:3][C:4](=[O:16])[C:5]=2[S:10][C:9]=1[C:11]1[CH:15]=[N:14][NH:13][CH:12]=1
Reactant: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1
Reactant: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)c(Br)c2N1
Temperature: 60 °C
Reaction time: 0.05 h
Yield: 30.6 %

Procedure:
To a solution of 2,2-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (248 mg, 1.00 mmol) in acetic acid (5 mL) was added slowly bromine (0.077 mL, 1.50 mmol) with vigorous stirring. After 3 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow solid. This residue was mixed with acetone (5.0 mL, 68.1 mmol), PTSA (9.5 mg, 0.050 mmol), MgSO4 (120 mg, 1.00 mmol) and DMF (1 mL). This mixture was stirred at 60° C. for 1 h. Then, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane to EtOAc) to give a pale yellow solid (100 mg). This solid was triturated with EtOAc and collected by filtration to afford the title compound (69.9 mg, 21%) as a pale yellow solid:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[C:38]=3[F:39])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 245. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.59 (s, 1H), 8.15-8.06 (m, 1H), 7.77 (s, 1H), 7.72-7.60 (m, 1H), 7.51-7.41 (m, 1H), 5.12-4.82 (m, 2H), 4.26-4.10 (m, 1H), 4.07-3.93 (m, 1H), 3.78 (s, 3H), 3.44-3.30 (m, 1H), 2.15 (ddd, J=11.7, 6.2, 3.5 Hz, 1H), 1.97-1.79 (m, 2H), 1.69 (d, J=13.1 Hz, 1H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:27]([CH2:29][CH2:30][CH2:31][C:32]#[CH:33])#[N:28]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]([CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[N:28]
Reactant: C#CCCCC#N
Reactant: O=C(NOCc1cccc(I)c1)c1ccccc1NCc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: N#CCCCC#Cc1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
The same procedure was used as described for the preparation of example 365, but without addition of tetrabutylammonium iodide. Starting materials: N-(3-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 361) and 5-cyano-1-pentyne (Aldrich).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][OH:14]>>[N:1]1[C:10]2[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCCc2cccnc21
Agent: Cl
Product: ON=C1CCCc2cccnc21
Yield: 96 %

Procedure:
According to the reported procedure (J. Het. Chem. 1978, 15, 249-251), 6,7-dihydro-5H-quinolin-8-one was reacted with hydroxylamine hydrochloride to afford the title compound (2.40 g, 96%) as a white solid after drying in vacuo: MS (ES) m/e 163 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: [O-]c1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2)cc1C#N
Yield: 49 %

Procedure:
The procedure of Example 35 was followed except that 1,2-dicyano-4-nitrobenzene (1.0 part) was used in place of the 1,2-dicyano-3-nitrobenzene, 1.0 parts instead of 2.79 parts of sodium phenoxide and 20 parts instead of 50 parts of dimethylformamide were used. 1,2-Dicyano-4-phenoxybenzene (0.6 parts, 49%) was obtained as a white solid, m.pt.98°-100° C.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1COCC1>[C:1]12([NH:11][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=CC(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 0.1 %

Procedure:
1-Adamantylamine (0.76 g; 5.0 mmol) and triethylamine (0.77 ml; 5.5 mmol) were dissolved in dry THF (40 mL) on an ice bath. After dropping acryloyl chloride (0.45 ml; 5.5 mmol) onto the solution, the mixture was stirred for 4 hours. After the reaction, the precipitate was removed by filtration, and the supernatant liquid was concentrated under reduced pressure. The resulting crude product was recrystallized from chloroform to give N-(1-adamantyl)acrylamide (0.85 mg; yield: 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8](=[O:18])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13]C(=O)C)[O:4][N:3]=1.C(N(CC)CC)C.Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH3:13])[O:4][N:3]=1
Reactant: CC(=O)CCCC(=O)CC(=O)Cc1cc(C)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1=C(c2cc(C)no2)C(=O)CCC1
Temperature: 0 °C
Yield: 39.4 %

Procedure:
1.2 g of 3-methylisooxazol-5-yl-2,4,8-nonanetrione obtained in Example 6 was dissolved in 15 ml of ethanol, and 0.53 g of triethylamine was added to it to stir at reflux for 8 hours. After cooling, the reaction solution was poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl-acetate layer was washed with water, dehydrated over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified on silica gel column chromatography to give 0.36 g of the title compound as white crystals. Melting point: 104-105° C.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1.ClCCl>O>[OH2:2].[C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[CH3:11][N:12]1[CH2:19][C@@H:18]2[C@@H:14]([N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[C:37](=[O:38])[CH:36]=[CH:35][CH:34]=[N:33]5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[CH2:13]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Temperature: 40 °C

Procedure:
2-{4′-[(3aR,6aR)-5-Methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one tartrate (Form A) was suspended in 1 mL of solution mixture, which was prepared by mixing 3.0 mL of dichloromethane with 1.5 mL of 20% water (in methanol). The suspension was vortexed and heated in a shaking water bath to about 40° C. and maintained for 1.5 hrs. It was further heated to about 70° C. The suspension was then filtered. The water bath was turned off, and the supernatant cooled to ambient temperatures naturally in the water bath. Single crystals were offered.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)=[O:15])([CH3:12])[CH3:11]>ClCCl>[Br:1][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:14]([O:13][C:10]([CH3:9])([CH3:11])[CH3:12])=[O:15])[CH:18]=2)[NH:22][C:21]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
N-Bromosuccinimide (0.095 g, 0.536 mmol) was added to a solution of ethyl 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.163 g, 0.536 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.186 g, 48%) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.97 (br. s., 1H), 7.70 (s, 1H), 7.28-7.39 (m, 2H), 6.54 (br. s., 1H), 4.33-4.54 (m, 2H), 1.54 (s, 9H), 1.39-1.48 (m, 3H). ES MS: m/z 381, 383.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][OH:16])=[O:11])[CH2:5][CH2:4]1)[CH3:2].C[C@H]1CC[C@H](NC([C@@H]2C[C@H]2C[O:31][S:32]([CH3:35])(=O)=[O:33])=O)CC1>>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][O:16][S:32]([CH3:35])(=[O:33])=[O:31])=[O:11])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1

Procedure:
Follow the procedure of Example 11d, and substitute trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-ethylcyclohexyl)-amide, Example 13c for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester therein, to obtain the title compound, m/z=304 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15]C(O)=O)[N:6]=[CH:5]2.C([N:21](CC)CC)C.ClC(OC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][NH2:21])[N:6]=[CH:5]2
Reactant: O=C(O)CCCn1ncc2cc(Br)ccc2c1=O
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCn1ncc2cc(Br)ccc2c1=O
Temperature: 0 °C

Procedure:
6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one (9.3 gm, 0.03 mole, prepared in Example XIV) was dissolved in 185 ml acetone by adding 4.7 ml triethylamine (0.0335 mole). The slightly cloudy solution was clarified, cooled to <10° C. and 3.8 gm methyl chloroformate (0.04 mole) was added over about 5 minutes. Stirred with cooling for another 30 minutes, then added a solution of 4 gm sodium azide (0.062 mole) in 25 ml water. Stirred for 30 minutes, added to 400 ml ice water and extracted three times with 80 ml methylene dichloride. This solution was dried, 4 ml of trifluoroacetic acid was added, and the solution refluxed for 18 hours. Methanol (100 ml) was added and the solution shaken with dilute potassium carbonate solution to free the base. The resulting solution was acidified with 10 ml of 30% HBr in acetic acid, diluted with 900 ml ether, filtered and washed with ethyl acetate. The product weighed 6.3 gm and showed a single spot on tlc, Rf =0.28 (using 10% methanol in chloroform on an ammonia treated silica plate).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:22][C:14]1[NH:15][C:16]3[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5](=[O:11])[NH:6]2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 4-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18].[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=[O:25])[CH2:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[F:11])=[CH:22][CH:21]=1
Reactant: Cc1ccncc1F
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1F)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium hexamethyldisilazide (1.0M in THF, 17.9 mL, 17.9 mmol) was cooled to 0° C. and 3-fluoro-4-methylpyridine (1.00 g, 0.926 mmol) in THF (50 mL) was added dropwise, keeping the solution temperature below 5° C. The mixture was then stirred for 1 hour at 0° C. and ethyl 4-fluorobenzoate in THF (50 mL) was added dropwise. The reaction was allowed to warm slowly to rt with stirring overnight. Aqueous ammonium chloride was added and the mixture was poured into EtOAc. The organic phase was separated dried (Na2SO4) and concentrated. Silica gel chromatography using a 10-50% EtOAc/heptanes gradient yielded 1.83 g (89%) of Ex 1-Step 6 product as a white solid: LCMS m/z 234.4 (M+1); 1H NMR (400 MHz, MeOH-d4) δ 8.41 (d, J=1.7 1H), 8.32 (d, J=4.8, 1H), 8.14 (dd, J=8.9, 5.4, 2H), 7.38 (dd, J=5.9, 5.1, 1H), 7.25 (dd, J=9.0, 9.0, 2H), 4.52 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][P:29](=[O:36])([O:33]CC)[O:30]CC)[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][P:29](=[O:30])([OH:33])[OH:36])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2c1ncccn1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)CN(c1ccc2c(c1)CCN2c1ncccn1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
70 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(1-pyrimidin-2-yl-2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 3 ml dichloromethane. Under argon 200 μl trimethylsilylbromide are added thereto and the mixture is refluxed for 2 hours. After cooling to ambient temperature 1 ml of methanol is added and the mixture is stirred for a further 1 hour. Then the solvents are eliminated in vacuo. The residue is taken up in 3 ml of methanol, stirred for 10 minutes and the solvent is eliminated in vacuo. The residue thus obtained is extracted from dichloromethane with 1% methanol. The solid is suction filtered and dried.
Reaction SMILES: [C:1]([C:3]1[C:8]([I:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[N:6]=[C:5]([S:14][CH3:15])[N:4]=1)#[N:2].O.[N-:17]=[N+:18]=[N-:19].[Na+].Cl>C(O)(C)C.[Br-].[Zn+2].[Br-]>[I:9][C:8]1[C:3]([C:1]2[N:17]=[N:18][NH:19][N:2]=2)=[N:4][C:5]([S:14][CH3:15])=[N:6][C:7]=1[C:10]([F:12])([F:11])[F:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1nc(C#N)c(I)c(C(F)(F)F)n1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CSc1nc(-c2nn[nH]n2)c(I)c(C(F)(F)F)n1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
4-Cyano-5-iodo-2-methylthio-6-trifluoromethylpyrimidine (0.50 g) was dissolved in isopropanol (5 ml) and added water (10 ml), sodium azide (0.19 g) and zinc bromide (0.16 g) with stirring in room temperature. The mixture was refluxed for 3 hr and then cooled to room temperature and then added 3N-HCl to acidify. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 5-iodo-2-methylthio-4-(2H-tetrazol-5-yl)-6-trifluoromethyl-pyrimidine (0.5 g) as colorless crystalline solid, mp 196-200° C.
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])O.C(Cl)Cl.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)Cl>[Cl-].[Na+].O>[Cl:5][S:1]([C:12]1[CH:11]=[CH:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:1]([Cl:5])(=[O:4])=[O:3])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:14][CH:13]=1)(=[O:4])=[O:3]
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(-c3ccc(S(=O)(=O)Cl)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
Under the nitrogen gas atmosphere, chloro sulfuric acid is diluted by adding chloro sulfuric acid (0.53 ml, 8 eq.) into methylene chloride (10 ml), and 1,1′:4′,1″-terphenyl (0.230 g, 1.0 mmol) is added gradually into a container in which diluted chloro sulfuric acid is contained keeping the temperature at 0° C., then stirred at the room temperature for 6 hours. The obtained reacted mixture is poured into brine, and deposited white insoluble is removed by suction filtration. Since the small amount of product is possible to be remained, the residue is washed well by methylene chloride. Then, this solution and the extracted solution are dried up using magnesium sulfate. Solvent is vaporized off under the vacuum condition, and the impurity is removed from the obtained crude product by isolating by a column chromatography (φ=50 mm, h=100 mm; CHCl3). Thus, 4,4″-dichlorosulfonyl1,1′:4′,1″-terphenyl (0.288 g, 0.67 mmol, 67%) is obtained as a colorless crystal (compound F).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(Cl)c2C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (3.84 g, 20 mmol) and DIPEA (5.2 mL, 30 mmol) in DMF was added tert-butyl piperazine-1-carboxylate (3.73 g, 20 mmol) portionwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue obtained was precipitated with H2O. The precipitate was collected, washed with water and dried in vacuo, to provide the title compound as a white solid in quantitative yield. MS (m/z) 342 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]OS(C)(=O)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]([OH:31])(=[S:30])[CH3:29]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20][S:30][C:28](=[O:31])[CH3:29])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(O)=S
Product: CC(=O)SCC(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Thioacetic acid S-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl]ester was prepared by an analogous procedure as described in example 26 ii) starting from 6.19 g (15.9 mmol) methanesulfonic acid 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl ester and 2.1 ml (1.8 equiv.) thioacetic acid. Purification by flash chromatography on silica gel (eluent: CH2Cl2) gave pure thioacetic acid S-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl]ester as yellow oil. Yield: 1.87 g MS (ES+): m/e=370.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14]>C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[Zn].[Cl-].[NH4+].O.C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14])=[C:2]([CH3:1])[CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(O)C(CO)Nc1ccc([N+](=O)[O-])cc1C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)C(CO)Nc1ccc(N)cc1C

Procedure:
The 2-[(2-methyl-4-nitrophenyl)amino]octadecane-1,3-diol (21) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]2[CH2:3][CH2:2]1.[C:15]1([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:31])=[CH:33][CH:34]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CN1CCC[C@H]1CN2
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine prepared in Reference Example 28 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give (11aS)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11, 11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The resulting (11aS)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine was dissolved in ethyl acetate, a 4N hydrochloric acid-ethyl acetate solution was added thereto, the resulting precipitates were recovered through filtration and washed with a small amount of ethyl acetate to thus give the title compound. Yield 62.4%.