Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][O:23][C:22]3=[O:31])[CH2:17][CH2:16]2)=[C:11]([Cl:32])[CH:10]=1.N1C=CC=CC=1>C(#N)C>[Cl:32][C:11]1[CH:10]=[C:9]([NH:8][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reaction time: 8 h

Procedure:
Isopropylsulphonyl chloride (0.03 ml) was added to a stirred solution of the product from example 120 step (ii) (0.05 g), pyridine (0.1 ml) in acetonitrile (0.9 ml) at room temperature. The mixture was stirred overnight, partitioned between ethyl acetate and water, the organics separated, washed with water, dried, and evaporated under reduced pressure. Purification was by chromatography eluting with 40% ethyl acetate/isohexane. Yield 0.015 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]#[N:18]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[N:18])[CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCN1
Reactant: N#CCBr
Product: CC1CN(Cc2ccccc2)CCN1CC#N

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-2-methyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=230.2: AtRet=1.86.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([Cl:16])=[O:7]
Reactant: O=C(O)/C=C/c1ccc(F)cc1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)cc1F

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][S:17][C:18]1[N:23]([CH3:24])[C:22](=[O:25])[C:21]([CH2:26][CH2:27]Cl)=[C:20]([CH3:29])[N:19]=1.[I-].[K+].C(N(CC)CC)C>C(#N)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH2:27][CH2:26][C:21]3[C:22](=[O:25])[N:23]([CH3:24])[C:18]([S:17][CH3:16])=[N:19][C:20]=3[CH3:29])[CH2:6][CH:5]=2)=[CH:8]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CSc1nc(C)c(CCCl)c(=O)n1C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc(C)c(CCN2CC=C(c3c[nH]c4ccccc34)CC2)c(=O)n1C
Temperature: 80 °C

Procedure:
To a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)indole (1.0 g, 5 mmol) in acetonitrile (30 ml) was added 2-methylthio-5-(2-chloroethyl)-3,6-dimethyl-3H-pyrimidin-4-one (1.42 g, 6.1 mmol), potassium iodide (0.84 g, 5 mmol) and triethylamine (1.4 ml, 10 mmol). The mixture was heated at 80° C. for 8 hours, cooled, concentrated and purified by flash chromatografy (dichloromethane/methanol/ammonia=95/4.5/0.5)
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=CC=2N=1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[C:38]3[S:52][C:51]([CH2:53][N:54]4[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]4)=[CH:50][C:39]=3[N:40]=[C:41]([C:43]3[CH:44]=[N:45][C:46]([NH2:49])=[N:47][CH:48]=3)[N:42]=2)[CH2:33][CH2:32]1.[CH3:60][S:61]([CH2:64][C:65](O)=[O:66])(=[O:63])=[O:62]>>[NH2:49][C:46]1[N:47]=[CH:48][C:43]([C:41]2[N:42]=[C:37]([N:34]3[CH2:33][CH2:32][O:31][CH2:36][CH2:35]3)[C:38]3[S:52][C:51]([CH2:53][N:54]4[CH2:55][CH2:56][N:57]([C:65](=[O:66])[CH2:64][S:61]([CH3:60])(=[O:63])=[O:62])[CH2:58][CH2:59]4)=[CH:50][C:39]=3[N:40]=2)=[CH:44][N:45]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)CC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was then reacted with methanesulfonylacetic acid via General Procedure B to generate 56 mg of 101. MS (Q1) 533.2 (M)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:17]([C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: O=[N+]([O-])c1cccc(Oc2ccccc2)c1

Procedure:
The compound above was prepared from 3-iodonitrobenzene (925 mg) and phenol, using the procedure described in Example 5 Step 1. The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:18]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[CH2:18]([N:25]([S:26]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 36901.3 %

Procedure:
The mixture was heated in an oil bath at 50° C. overnight and then was heated in an oil bath at 100° C. for 1.5 days. The mixture was poured into 800 ml of water and extracted with ethyl acetate. The extract was washed with water, 2N citric acid, water, brine and dried (Na2SO4). The solvent was removed and the residue chromatographed on silica gel with hexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as a solid, mp 170-1720. From a larger scale run of 5.07 g (0.02 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 8.0 g (0.0289 mmol) of benzyl-(4-methoxybenzenesulfonyl) amine (as sodium anion) in 30 ml of 1-methyl-2-pyrrolidinone heated at 90° C. for 3 days there was obtained 3.65 g of product.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[N:50]1[CH2:54][CH2:53][CH2:52][C:51]1=[O:55])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[N:50]1[CH2:54][CH2:53][CH2:52][C:51]1=[O:55])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)=C(N1CCCC1=O)CC2
Reactant: [H][H]
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](Cc1ccccc1)[C@@H](N1CCCC1=O)CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (3.70 mg, 15.0 μmol of Rh), Josiphos SL-J216-2 (10.16 mg, 16.0 μmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)pyrrolidin-2-one (500.8 mg, 1.50 mmol) were combined in a glass-lined metal reactor, and the vessel was inerted with argon. Degassed methanol (5.0 ml) was added, and the mixture was agitated under 20 psi of argon at 50° C. for 20 min. The vessel was pressurized with 90 psig of hydrogen and stirred at 100° C. for 45 hrs. HPLC analysis indicated 99.8% conversion and 90.7% ee. The mixture was concentrated and diluted with water to yield 415 mg (yield: 82%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:28])([F:27])[CH2:15][CH:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17].[I:29]I>O1CCCC1>[F:28][C:14]([F:13])([F:27])[CH2:15][C:16]([I:29])([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: CC(CC(F)(F)F)S(=O)(=O)c1ccccc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(I)(CC(F)(F)F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of 28.5 mmol diisopropylamine in 18 ml tetrahydrofuran at −78° C. was added dropwise 28.5 mmol n-butyllithium solution (1.6 M in hexane) and the mixture was then warmed to room temperature. The resulting solution was then added dropwise over 50 min to a solution of 19.0 mmol rac-(4,4,4-trifluoro-butane-2-sulfonyl)-benzene in 30 ml tetrahydrofuran at −78° C. and stirring continued for a further 15 min at −78° C. Finally, a solution of 20.9 mol iodine in 15 ml tetrahydrofuran was added dropwise over 15 min and stirring continued for a further 15 min at −78° C. and then the reaction mixture was allowed to warm to −20° C. The reaction mixture was quenched by addition of 1 M hydrochloric acid and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed sequentially with aqueous sodium thiosulfite solution and with brine and then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow oil (yield 87%). EI-MS (m/e): 377.9 (M+, 4%), 237.0 ([M−PhSO2]+, 40%), 142.0 (PhSO2H+, 100%), 125.1 (PhSO+, 93%), 78.2 (PhH+, 40%), 77.2 (Ph+, 31%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CC1NC(C)=C(C([O-])=O)CC=1C([O-])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: CC1=C(C(=O)[O-])CC(C(=O)[O-])=C(C)N1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 56.9 %

Procedure:
Under a nitrogen atmosphere, 13.98 g of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-2-thioxo-4-thiazolidinone, 13.17 g of die 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and 600 ml of toluene were stirred to effect solution. Forty grams of silica gel 60 (finer than 230 mesh), previously dried in vacuo at 50° C. for 7 hours, were added to the reaction. The reaction was heated at reflux for 18 hours and filtered hot. The filtrate was evaporated to dryness. The residue was dissolved in 500 ml of ethyl acetate, washed 5 times each with 400 ml of 1N hydrochloric acid, dried over sodium sulfate, filtered, and evaporated in vacuo to provide a yellow solid. Chromatography over silica gel eluting with 2.5% ethyl acetate in toluene provided 8.0 g of title product, m.p 178°-179° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([C@H:7]1[C@@H:12]2[O:13]S(=O)O[C@@H:11]2[CH:10]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH2:8]1)=[CH2:6]>CN(C=O)C.CCOC(C)=O>[N:1]([C@@H:11]1[C@@H:12]([OH:13])[C@H:7]([CH:5]=[CH2:6])[CH2:8][C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C[C@@H]1CC(C(=O)OC)=C[C@H]2OS(=O)O[C@@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide can be added to a solution of Example 17G in DMF. The reaction mixture can be stirred overnight at room temperature, diluted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: [Br:1]C1(Br)NC(=O)NC1=O.[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH3:21].CC(N=NC(C#N)(C)C)(C#N)C.CC(=O)OCC>ClC1C=CC=CC=1>[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH2:21][Br:1]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O=C1NC(=O)C(Br)(Br)N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reaction time: 1 h

Procedure:
A mixture of dibromohydantoin (70 g, 0.24 mol) and AlBN (5 g) was added in portions at 150° C. to 2,6-dichloro-3-nitrotoluene (100 g, 0.48 mol) in chlorobenzene (400 ml). After 1 h, a mixture of dibromohydantoin (35 g, 0.12 mol) and AIBN (2.5 g) was again added. After a further 1.5 h, the mixture was allowed to cool and EA (500 ml) was added. This mixture was washed once each with saturated Na2SO3, Na2CO3 and NaCl solution, dried (MgSO4) and concentrated, the title compound being obtained as an amorphous powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[C:17]([F:23])[C:16]=1[F:24]>CN(C=O)C.C(#N)C>[CH3:14][C:15]1[C:20]([F:21])=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([F:23])[C:16]=1[F:24]
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Temperature: 75 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 3-trifluoromethyl phenol (13.2 ml, 0.11 mol) in anhydrous DMF (200 ml) is added sodium hydride (4.8 g, 60%, 0.12 mol). After 30 min at ambient temperature the solution is added to another solution of 4-methyl-2,3,5,6-tetrafluoropyridine (16.5 g, 0.1 mol) in anhydrous acetonitrile (700 ml) at 50° C. during 3 hours. The resulting mixture is then stirred for 1 hour at 50° C. and 16 hours at 75° C. The solvents are removed in vacuo and to the residue is added ethyl acetate/pentane (1000 ml, 1/1 by volume). The mixture is washed twice with 2 M NaOH and 5 times with water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains a colorless oil (23.3 g, 76 mmol, 76% yield, bp. 76° C. at 0.025 mbar) of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:4]=2[S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][Br:15])[CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: Cc1ccc2c(c1)C(=O)N(C)S2(=O)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)c2cc(CBr)ccc2S1(=O)=O

Procedure:
A solution of 2,5-dimethyl-1,1-dioxo-benzo[d]isothiazole-3-one (5.8 g) in carbon tetrachloride (100 ml) containing 2,2-azo-bis(2-methyl-propionitrile) (50 mg) and 4.8 g of N-bromosuccinimide was heated at reflux for about 2 hours.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:37][CH:34]3[CH2:36][CH2:35]3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCN(C2CCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[N:13]1[S:14][N:15]=[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=12.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:22][C:20]1[CH:19]=[CH:18][C:17]2=[N:13][S:14][N:15]=[C:16]2[CH:21]=1)[CH3:2]
Reactant: Oc1ccc2nsnc2c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 81.9 %

Procedure:
A mixture of 2-chloro-nicotinic acid ethyl ester (0.516 g, 3 mmol), benzo-[2,1,3]-thiadiazol-5-ol (0.46 g, 3 mmol) and cesium carbonate (2.07 g, 6.3 mmol) was stirred in 40 mL N,N-dimethylformamide at 80° C. for 48 hours. The dark orange mixture was cooled and poured into water (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried (Na2SO4). The mixture was concentrated in vacuo to give 0.74 g yellow solid (82% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.CO.[N+](C1C=CC(OC(=O)[NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH:55]([CH3:57])[CH3:56])=[CH:50][CH:49]=2)=CC=1)([O-])=O>>[CH:55]([O:54][C:51]1[CH:52]=[CH:53][C:48]([NH:47][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:49][CH:50]=1)([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCOS(C)(=O)=O)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To 4-[7-(3-methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 115, was added 3M HCl/MeOH (2 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitrophenyl ester (0.11 mmol), which was prepared as described in Example 1a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH; 9.5:0.5) to obtain 40 mg (75%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.12 (s, 1H), 8.05 (d, 1H), 7.32-7.20 (m, 4H), 6.81 (d, 2H), 6.53 (s, 1H), 4.50-4.40 (m, 3H), 4.25 (t, 4H), 3.72-3.59 (m, 1H), 3.16-3.03 (m, 2H), 3.01 (s, 3H), 2.36-2.26 (m, 2H), 2.18-2.00 (m, 2H), 1.99-1.87 (m, 2H), 1.29 (d, 6H). LC/MS (ESI): 543.1 (MH)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:31])([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:31])([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Agent: [Na+]
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Yield: 84.1 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methyl-2-(3-phenylpropyl)propionate (1.16 g), which is the product of Reference example 7(g), and sodium azide (0.50 g) and the reaction mixture was treated to afford the desired compound (0.86 g) as a syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[S:27][C:26]([NH:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[S:27][C:26]([NH:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[N:25][CH:24]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cnc(NCC2CC2)s1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnc(NCC4CC4)s3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.202 g, 0.617 mmol) and N-(5-bromothiazol-2-yl)-cyclopropylmethylamine (0.14 g, 0.62 mmol) in anhydrous DMF (6.2 mL) at room temperature add cesium carbonate (0.22 g, 0.68 mmol). Stir at room temperature overnight and partition the reaction mixture between saturated aqueous NaHCO3 (50 mL) and DCM (100 mL). Dry the organic extract over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to an Analogix® column (40 g) and purify the crude intermediate by preparative liquid chromatography (100:0 to 75:25 hexane/EtOAc over 30 min; 75:25 to 50:50 hexane/EtOAc over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.129 g, 44%). MS (ES+) m/z: 480.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[Br:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1
Reactant: BrCCBr
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1ccccc1-c1nc(-c2ccccc2)no1

Procedure:
1.85 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 80 ml of methylethylketone, mixed with 5 ml of 1,2-dibromoethane, 6 g of potassium carbonate and 0.1 g of potassium iodide. The mixture is refluxed for 12 hours and after cooling the precipitate is filtered off. The organic phase is evaporated down in vacuo and chromatographed on silica gel first with toluene, then with dichloromethane as eluant. Yield: 2.3 g (86% of theory).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][CH2:7][C:8]([O:10]CC)=O.Cl.[O-:17][C:18]#[N:19].[Na+]>>[I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:7][C:8](=[O:10])[NH:19][C:18]1=[O:17]
Reactant: N#C[O-]
Reactant: CCOC(=O)CNCc1cccc(I)c1
Agent: Cl
Agent: [Na+]
Product: O=C1CN(Cc2cccc(I)c2)C(=O)N1
Yield: 96.7 %

Procedure:
Ethyl N-(3-iodobenzyl)glycinate (0.567 g) was treated with 1M HCl (3.9 ml) and sodium cyanate (0.345 g) and then refluxed for 30 min. Concentrated HCl (4.5 ml) was added and the reaction mixture refluxed again for 30 min. The reaction mixture was evaporated under reduced pressure and then triturated with EtOAc (3×20 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound (0.543 g). LCMS RT 2.63 min.