Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[C:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=1)=[O:29])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)NC(=O)CN(C(=O)CN)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)NC(C)(C)C)c2ccccc2)c1
Yield: 66.4 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.0 g of 2-(2-amino-N-phenylacetamido)-N-tert-butylacetamide and 0.55 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 1.0 g of N-tert-butyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 214° C. is obtained.
Reaction SMILES: ClCCl.[OH:4][C@H:5]([CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C:27]2=[O:32])=[CH:22][CH:21]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:33](=O)([O-])[O-:34].[K+].[K+]>O1CCCC1>[O:34]=[C:33]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:18][C@H:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[O:4]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In a four neck round bottom flask, charged dichloromethane (150 ml), 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (15 g), N,N′-dicarbonyldiimidazole (9.22 g), and powdered potassium carbonate (5.24 g) at 25 to 30° C. The obtained reaction mass then stirred for 5 h at 25 to 30° C. Reaction mass then filtered and obtained solid is washed the by dichloromethane. Separated filtrate is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (30 ml) to residue. The obtained mixture is heated to 40 to 45° C. for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran. Yield 90%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21]>>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (IX) is reacted with a thiocyanate and then with a halogen to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (X).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Cl[Si:12]([CH3:27])([CH3:26])[CH:13]1[C:21]2[S:22][C:23]([CH3:25])=[CH:24][C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2>CCOCC.CCCCCC>[C:1]([NH:5][Si:12]([CH3:26])([CH3:27])[CH:13]1[C:21]2[S:22][C:23]([CH3:25])=[CH:24][C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1cc2c(s1)C([Si](C)(C)Cl)c1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc2c(s1)C([Si](C)(C)NC(C)(C)C)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.93 mL (0.0089 mol) of tert-butylamine in 30 mL of ether was treated dropwise with 5.55 mL (0.0089 mol) of 1.6M BuLi in hexane at −30° C. The reaction mixture was stirred at r.t. for 3 h and the resulting suspension was treated with a solution of 2.47 g (0.0088 mol) of chloro(dimethyl)(2-methyl-8H-indeno[2,1-b]thiophen-8-yl)silane in 10 mL of ether at −70° C. The resulting suspension was allowed to warm to r.t. and was stirred overnight. The solution was separated from LiCl and evaporated. The residue was treated with 60 mL hexane, the solution was isolated and evaporated. Yield 1.98 g (71%) of crude product as red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:14]C.[Br:16]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:4]1[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:14]
Reactant: COc1ccc(S(F)(F)(F)(F)F)cc1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
5.30 g of 2-chloro-1-methoxy-4-pentafluorosulfanylbenzene were dissolved in 150 ml of CHCl3 and admixed with 4.73 g of bromine and 638 mg of FeBr2. The mixture was stirred at RT for 18 hours, then admixed with a further 200 mg of FeBr2, stirred at RT for 6 hours and then admixed with a further 300 mg of FeBr2, stirred at RT for 2 hours and left to stand at RT for 18 hours. The reaction mixture was then poured onto 300 ml of a saturated aqueous Na2SO3 solution and extracted with 300 ml of CH2Cl2. The organic phase was then washed with 100 ml of water and dried over Na2SO4, and the solvent was removed under reduced pressure. 4.20 g of a colorless oil were obtained which was reacted further without purification.
Reaction SMILES: CC(C)([O-])C.[K+].C([O:9][C:10](=[O:18])[CH2:11][N:12]=[C:13]([S:16][CH3:17])[S:14][CH3:15])C.[C:19]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)([CH3:22])([CH3:21])[CH3:20].[OH-].[Na+].Cl>C1COCC1.O>[CH3:17][S:16][C:13]([S:14][CH3:15])=[N:12][C@H:11]([C:10]([OH:9])=[O:18])[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=1
Reactant: CCOC(=O)CN=C(SC)SC
Reactant: CC(C)(C)c1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(=N[C@@H](Cc1cccc(C(C)(C)C)c1)C(=O)O)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.78 g (15.8 mmol) of potassium t-butoxide in 30 ml of THF, a solution of 3.28 g (15.8 mmol) of N-[bis(methylthio)methylene]glycine ethyl ester (Angew. Chem. Internat. Edit., 14, 426 (1975)) and 2.39 g (10.5 mmol) of 3-t-butylbenzyl bromide (Eur. J. Med. Chem., 23, 477 (1988)) in 10 ml of THF was added at −78° C. and the mixture was stirred at room temperature for 1 hour. Under cooling with ice, 10 ml of water was added, then 5 ml of 2 N aqueous sodium hydroxide was added and the mixture was stirred at room temperature for another 1 hour. Under cooling with ice, 2 N hydrochloric acid was added to the reaction mixture to render it acidic; the reaction mixture was extracted with chloroform and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate) to give N-[bis(methylthio)methylene]-3-t-butylphenylalanine in the amount of 577 mg (16%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Pyridine (4 ml) was added to 0.4 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 8 ml of acetic anhydride. At the room temperature, the resulting mixture was stirred for 4 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The extract was next dried over anhydrous Na2SO4 and the chloroform was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (100:1), 0.3 g of 8-cyano-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)[CH:31]=[CH:32][C:27]=1[F:26])=[O:37]
Reactant: COC(=O)c1cc(B(O)O)ccc1F
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Product: COC(=O)c1cc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)ccc1F

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and (4-fluoro-3-methoxycarbonylphenyl)boronic acid was prepared the title compound as a yellow oil, MS (ESI+): m/z=468.1977 ([M+H]+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CN(C(=O)CO)C[C@H]1O

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[O:15]COC)=[CH:4][C:3]=1[CH:21]1OCC[O:22]1.Cl.O>O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[OH:15])=[CH:4][C:3]=1[CH:21]=[O:22]
Reactant: COCOc1cc(C#N)ccc1Oc1ccc(Br)c(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)c(O)c1
Yield: 102.3 %

Procedure:
To a solution of 4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-methoxymethoxybenzonitrile (32.2 g, 79.3 mmol) in tetrahydrofuran (300 mL) was added 3 M HCl (100 mL), and the mixture was refluxed for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-(4-bromo-3-formylphenoxy)-3-hydroxybenzonitrile (25.8 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C@@H:6]([CH3:19])[N:5]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[N+:14]([O-:34])[CH:15]=[CH:16][CH:17]=3)[C:7](=[O:18])[C@@H:6]([CH3:19])[N:5]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:4]=2[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1C(=O)N(c2cccnc2)c2cnc(Cl)nc2N1C1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2ccc[n+]([O-])c2)c2cnc(Cl)nc2N1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
To a stirred solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-5-(pyridin-3-yl)-7,8-dihydropteridin-6(5H)-one (51.2 mg, 0.143 mmol) in dichloromethane (2.5 mL) was added mCPBA (77% max, 33.7 mg, 0.150 mmol) at rt, and the solution was stirred at rt. More mCPBA (77% max, 10.2 mg, 0.0455 mmol) was added after 2.5 h, and stirring at rt was continued for additional 4 h. The reaction solution was diluted with dichloromethane (15 mL), washed with aq. NaHCO3 solution (20 mL×2), dried over Na2SO4, and concentrated in vacuo to give a crude residue, which was then purified by silica gel column chromatography (eluent: 5% methanol in dichloromethane) to give the desired product (0.116 mmol, 81% yield). 1H NMR (CDCl3, 400 MHz): δ 8.30 (d, J=6.8 Hz, 1H), 8.17 (s, 1H), 7.45 (dd, J=8.4, 6.8 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 4.49 (q, J=6.8 Hz, 1H), 4.49-4.39 (me, 1H), 2.17-2.10 (m, 1H), 1.96-1.87 (m, 2H), 1.83-1.64 (m, 3H), 1.55-1.43 (m, 3H), 1.47 (d, J=6.8 Hz, 3H), 1.25-1.14 (m, 1H). MS(ES+): m/z=374.13/376.21 [MH+].
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[CH3:60][NH:61][C:62](=[O:73])[NH:63][C:64]1[S:65][C:66]2[CH:71]=[CH:70][N:69]=[CH:68][C:67]=2[N:72]=1.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CN(C=O)C.CCOCC.C([O-])(=O)C>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:69]4[CH:70]=[CH:71][C:66]5[S:65][C:64]([NH:63][C:62]([NH:61][CH3:60])=[O:73])=[N:72][C:67]=5[CH:68]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CNC(=O)Nc1nc2cnccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(=O)[O-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNC(=O)Nc1nc2c[n+](CC3=C(C(=O)[O-])N4C(=O)C(NC(=O)/C(=N\OC)c5csc(N)n5)[C@H]4SC3)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-(3-methylureido)-thiazolo[4,5-c]pyridine (104 mg, 0.5 mmole) in 3 ml of dry DMF was stirred at room temperature for 1 hour and diluted with ether acetate to give 430 mg of crude quaternary salt, which was treated with TFA and anisole at room temperature for 30 minutes. The mixture was evaporated and triturated with ether to give 302 mg of crude Ir which was purified on a column of HP-20 resin (40 ml) using 30% CH3OH as an eluant to give 169 mg (56%) of Ir. Mp. 184°~200° C. (dec.). Estimated purity by HPLC: 40%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([Cl:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([Cl:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: Cc1c(F)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To the thus obtained 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-chloro-5-nitrotoluene (0.13 g) are added anhydrous dimethylformamide (2 ml), potassium fluoride (37 mg) and cyclopropylamine (0.15 ml) and the mixture is stirred at 100° C. for 3 hours. After cooling, the reaction mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and purified by silica-gel column-chromatography (eluent; dichloromethane: methanol=10:1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-5-chloro-2-methyl-6-nitro-N-cyclopropylaniline (0.14 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]([C:22]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:23])[CH:18]([CH3:19])[CH2:20][CH3:21])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Yield: 70.7 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 3-(aminomethyl)pyridine, 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.95 g of BOP, 11.95 g of Hunig's base and 15 ml of methylene chloride to give 2.1 g of the desired product after chromatography.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8].[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8]
Reactant: NCCS
Reactant: Cc1snnc1CO
Product: Cc1snnc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[(2-aminoethyl)thiomethyl]-5-methyl-1,2,3-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].I[CH:31]([F:33])[CH3:32].O>C(#N)C>[F:33][CH2:31][CH2:32][N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:19][CH2:20]1
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: CC(F)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 89, step D) (0.958 g, 2.99 mmol) and Na2CO3 (0.470 g, 4.43 mmol) in acetonitrile (20 mL) was added iodofluoroethane (0.500 mL, 6.15 mmol) in one portion. The resultant mixture was heated at 70° C. for 48 h. When complete by TLC, the reaction was poured into H2O (150 mL), extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.972 g, 2.63 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H), 1.70 (d, J=15.0 Hz, 2H), 1.94 (t, J=12.5 Hz, 2H), 2.12-2.21 (m, 1H), 2.50 (t, J=5.0 Hz, 1H), 2.52-2.58 (m, 5H), 2.88 (d, J=10.4 Hz, 2H), 3.35-3.40 (m, 4H), 3.86 (s, 3H), 4.46 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 6.54 (dd, J=9.3, 2.1 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].B(O)(O)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: C=Cc1ccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)cc1
Yield: 37.3 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 4-vinylboronic acid (22.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(4-vinyl-phenyl)-thiazole-5-carboxylic acid (15.2 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.69 (br.s., 1 H); 8.82 (s, 1 H); 7.95 (d, 2 H); 7.84 (s, 1 H); 7.60 (d, 2H); 7.39 (s, 1H); 6.82 (dd, 1 H); 5.97 (dd, 1 H); 5.37 (dd, 1 H); 3.86 (s, 3 H); 3.86 (s, 3 H). MS 408 m/z (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:25]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[N:20]=[CH:19]3)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ncc3c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a stirred suspension of NaH (60%, 4 mg, 0.1 mmol) in DMF (0.5 mL) was added dropwise a solution of 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.100 g, 0.33 mmol) in DMF (1 mL). After stirring for 30 minutes, methyl iodide (0.026 g, 0.18 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-(1-Methyl-1H-indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.023 g, 22%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.87 (s, 1H), 7.32 (d, J=9.2 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.12 (s, 1H), 4.04 (s, 3H), 3.62 (m, 4H), 3.09 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 317 [M+H]+; Rt=3.31 minutes.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([O:28]C)=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>CO.O1CCCC1.[OH-].[K+]>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CC(=O)OC)cc1OCCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CC(=O)O)cc1OCCCCCCCC
Yield: 103.6 %

Procedure:
Methyl 2-[3,4-bis(octyloxy)phenyl]acetate (3.94 g, 9.69 mmol) was dissolved in a mixture of methanol (30 ml) and tetrahydrofuran (30 ml), and 1N potassium hydroxide (19 ml) was added thereto. After being refluxed for 3 hours, the mixture was acidified with 3N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated out, to give 2-[3,4-bis(octyloxy)phenyl]acetic acid (3.94 g, 89%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to example 724. Product was isolated as a tan solid (0.024 g, 12%). Mp 90-94° C.; LCMS (m/e) 529 (M); 1H-NMR (DMSO, 400 MHz) δ 9.47 (s, 1H), 9.43 (s, 1H), 8.59 (m, 1H), 8.29 (s, 1H), 7.86-7.84 (d, 1H, J=7.83 Hz), 7.72 (t, 1H, J=8.08 Hz), 7.40-7.36 (t, 1H, J=7.83 Hz), 7.15 (s, 1H), 7.01-6.95 (d, 1H, J=8.33 Hz), 3.61-3.52 (m, 2H), 3.47-3.45 (q, 2H, J=6.32 Hz), 2.96-2.90 (m, 5H), 2.80-2.70 (m, 2H), 1.23-1.17 (d, 6H, J=6.82 Hz), 1.08-0.98 (t, 6H, J=6.82 Hz).