Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccc(F)c(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-4-fluoro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chloro-4-fluorobenzaldehyde. Mass spectrum (ES) MH+=323.
Reaction SMILES: [Li].[F:2][C:3]1[CH:4]=[C:5]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[N:7][CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][NH2:51])[CH:46]=[CH:47][C:48]=1[F:49]>>[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([F:2])[CH:4]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:51]2)[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(F)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.42 g (4.33 mmol) of the compound of Example 13A is reacted analogously to the synthesis of the compound of Example 20A with 1.28 g (6.50 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 854 mg (59% of theory) of the title compound is obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]=1[N+:21]([O-:23])=[O:22].[C:24]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[N+:21]([C:9]1[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Yield: 78.6 %

Procedure:
K2CO3 (4.04 g, 29.22 mmol) was added to a solution of 1-chloro-2,4-dinitronaphthalene (6.04 g, 23.91 mmol) and t-butyl ethyl malonate (5.0 g, 26.50 mmol) in THF (50 mL), and the mixture was heated reflux overnight. The mixture was cooled and filtered, then the filtrate was concentrated under reduced pressure. Flash chromatography (20-50% AcOEt-Petroleum ether gradient elution) afforded t-butyl ethyl (2,4-dinitronaphthalen-1-yl)malonate (7.6 g, 54%) as a pale red solid. M.p. 86-88° C.; 1H NMR (CDCl3, 500 MHz) δ 8.65 (s, 1H), 8.55 (dd, 0.5, 8.5, 1H), 8.36 (dd, 0.5, 9.0, 1H), 7.89 (dt, 1.0, 8.0, 1H), 7.81 (dt, 1.5, 9.0, 1H), 5.64 (s, 1H), 4.26 (q, 7.0, 2H), 1.44 (s, 9H), 1.24 (t, 7.0, 3H); IR (neat) 2980, 1745, 1537, 1368, 1346, 1306, 1253, 1147, 1027, 850, 832, 801, 774, 761 cm−1. FABMS (NBA) m/z 405 (M+H+, 5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([F:20])[C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]1[CH:16]=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[C:13]([F:20])[C:14]=1[O:18][CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)cc(-c2ccncc2)cc1F

Procedure:
In a microwave vial, a mixture of pyridin-4-ylboronic acid (160 mg, 1.3 mmol), 5-bromo-1,3-difluoro-2-methoxybenzene A5a (223 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) is dissolved/suspended in dimethylformamide (3 mL). To the mixture are added cesium carbonate (978 mg, 3 mmol) and water (3 mL). The vial is sealed and subjected to microwave irradiation (150° C., 15 min). The mixture is filtered through a syringe filter and washed with ethyl acetate. Water is added and the mixture extracted with ethyl acetate (4×). The organic phase is dried over sodium sulfate and concentrated. The crude material is purified by flash chromatography (ethyl acetate/hexanes gradient) to afford 4-(3,5-difluoro-4-methoxyphenyl)pyridine A5b as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=6 Hz, 2H), 7.44 (d, J=6 Hz, 2H), 7.22 (d, J=9.6 Hz, 2H), 4.09 (s, 3H); MS calcd. for C12H10F2NO ([M+H]+): 222.1, found: 222.1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]1>>[O:26]=[S:23]1(=[O:27])[CH2:24][CH2:25][N:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:22]1
Reactant: O=S1(=O)CCNCC1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Product: COc1ccc(Nc2nc3c(N4CCS(=O)(=O)CC4)cccn3n2)cc1

Procedure:
8-(1,1-dioxidothiomorpholin-4-yl)-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and thiomorpholine 1,1-dioxide (25.0 mg, 0.185 mmol) in a manner analogous to Example 30. Product isolated as a tan solid (0.052 g, 89%). MP=231-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.4, 1.1 Hz, 1H), 7.50-7.45 (m, 2H), 6.94-6.89 (m, 2H), 6.77 (dd, J=7.7, 6.7 Hz, 1H), 6.73 (dd, J=7.6, 0.9 Hz, 1H), 6.57 (s, 1H), 4.12-4.06 (m, 4H), 3.81 (s, 3H), 3.28-3.23 (m, 4H). MS=374 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH2:23])[C:17]=2[N:16]=[CH:15]1.[N+](C1C2N=CSC=2C=CC=1)([O-])=O.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:17]=2[N:16]=[CH:15]1
Reactant: Nc1cccc2scnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1cccc2scnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2scnc12
Yield: 45.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzenesulfonyl chloride (1.7 g, 7.9 mmol), benzothiazol-4-ylamine (Intermediate 222) (1.0 g, 6.6 mmol), DMAP (cat), pyridine (2 ml, 24.8 mmol) and DCM (10 ml) at 0° C. for 5 h, gave the title compound (1.0 g, 45%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:36])=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 83 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with benzyl-methyl-amine to give 69 mg of {4-[(benzyl-methyl-carbamoyl)-methyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C27H33N3O5+H 480.6; found 480.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([OH:10])=[C:4]2[CH:3]=[N:2]1.[Br:11]Br>O>[Br:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[OH:10])[NH:1][N:2]=1
Reactant: BrBr
Reactant: Oc1ncnc2[nH]ncc12
Solvent: O
Product: Oc1ncnc2[nH]nc(Br)c12
Temperature: 91 °C
Yield: 9.5 %

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-ol (10 g, 73.5 mmol) was suspended in 700 ml of water. Bromine (10 ml, 194 mmol) was added and the resulting reaction mixture was heated to 91° C. overnight. After cooling on ice-water, the solid was collected by filtration to give 1.508 g of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol as light yellow solid. 1H NMR (DMSO) 8.06 (s 1H), 12.25(bs, 1H), 14.06 (bs, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH3:29]CN(C(C)C)C(C)C.Cl.C(=N)OC(C)C>CO>[N:4]1([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2][N:1]=[CH:29]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)OC=N
Agent: Cl
Solvent: CO
Product: O=C(C[C@H]1CC[C@H](N2C=NCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 15) in MeOH was added DIEA (2.5 eq), followed by isopropyl formimidate hydrochloride (1.2 eq). The reaction mixture was stirred at RT overnight. The mixture was then concentrated in vacuo and the crude product was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 400 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:3]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1-c1ccc(F)cc1
Yield: 84.5 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 2-bromoanisole (8.91 g), 4-fluorophenylboronic acid (10.0 g), 2M aqueous sodium carbonate solution (47.6 ml) and tetrakis(triphenylphosphine)palladium(0) (2.20 g), the title compound (8.14 g) was obtained as colorless needle crystals.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCN(CC)CC.[C:18](=S)=[S:19].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[N:10]([C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])=[C:18]=[S:19]
Reactant: S=C=S
Reactant: CC(C)(N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(N=C=S)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cumylamine (5.32 mL, 37.0 mmol) (TCI America) and Et3N (16.97 mL, 122 mmol) (Aldrich) were mixed in THF (40 mL) at 0° C. under a nitrogen atmosphere. Carbon disulfide (2.224 mL, 37.0 mmol) (J.T.Baker) was added dropwise via syringe over the course of 10 min. The reaction was stirred at 0° C. for 1 h before being warmed to RT and stirred for 1 h. p-Toluenesulfonyl chloride (7.76 g, 40.7 mmol) (Fluka) was added, and the reaction was stirred at RT for 1 h. The mixture was quenched with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give (2-isothiocyanatopropan-2-yl)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14](N)[CH2:15][NH2:16]>O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:5]1[CH2:14][CH2:15][N:16]=[C:4]1[C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH2:1]
Reactant: NCCN
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: COc1cc(N)c(C2=NCCN2)cc1OC
Reaction time: 8 h
Yield: 82.3 %

Procedure:
2-Amino-4,5-dimethoxybenzonitrile (5.0 g, 28 mmol) was added to ethylenediamine (7.9 g, 131 mmol) at room temperature. The resulting solution was warmed to 40, and a catalitic amount of diphosphorus pentasulfide (50 mg) was added. The mixture was heated to 80-90, and the stirring was continued overnight. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to give 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (5.1 g, 82%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1
Reactant: CCCN(CCC)CCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.1 %

Procedure:
An anhydrous methanol solution (4.0 ml) containing the compound (0.244 g) obtained in Example 46-6 and 2-imidazole carboxaldehyde (85.0 mg) was added with trimethyl orthoformate (0.242 ml). The whole was stirred at room temperature for 14 hours and then added with sodium borohydride (0.140 g). After the solution was stirred for 2 hours, the solvent was distilled off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (0.167 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13]([CH3:16])([OH:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:24])C(=O)C1.CN(C=O)C>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][C:10]=2[I:24])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Solvent: CN(C)C=O
Product: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.20 g, 9.26 mmol) and NIS (2.71 g, 12.0 mmol) were dissolved in DMF (36.6 mL, 0.472 mol) and stirred at 60° C. for 4 h. The mixture was then concentrated in vacuo and the residue reconstituted in EtOAc (100 mL). This solution was washed with sodium bicarbonate (2×20 mL) and these washes back-extracted with EtOAc (2×20 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc:hexanes to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 3 H), 2.72-2.59 (m, 4 H), 3.37-3.29 (m, 1 H), 7.32 (d, J=4.91 Hz, 1 H) and 7.60 (d, J=4.96 Hz, 1 H). MS (ES+): m/z 363.95 and 365.91 [MH+].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][C:13]([S:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:18][S:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 4.07 g, 26.1 mmol) and 2-methyl-propane-2-sulfinic acid amide (Aldrich, 3.16 g, 26.1 mmol) in THF (20 mL) was added Ti(OEt)4 (Aldrich, 10.8 mL, 52.2 mmol) at room temperature. The reaction was stirred overnight and quenched with ˜5 mL water until precipitation completed. The solid was filtered off and washed with additional ethyl acetate. The combined filtrate was dried over anhydrous Na2SO4, filtered, concentrated and the residue was purified by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[CH3:13].[H-].[Na+].I[CH3:17].N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([N:7]([CH3:17])[C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1C
Reactant: CI
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4'-methoxy-3'-methylacetanilide (71g) in dry tetrahydrofuran (350 ml) was added over 45 minutes to a stirred suspension of sodium hydride (19 g of a 50% dispersion in mineral oil) in dry tetrahydrofuran (250 ml) under nitrogen. The stirred mixture was heated under reflux for 10 minutes, then cooled to 0 to 5° and iodomethane (25 ml) added dropwise over 10 minutes. After the mixture was stirred and heated under reflux for a further 2 hours, the mixture was cooled to ambient temperature and industrial methylated spirit (50 ml) followed by aqueous ammonia (specific gravity 0.88, 50 ml) were added. After 30 minutes, solvent was removed by evaporation, water (500 ml) added to the residue and the mixture extracted with ethyl acetate (3×300 ml). The combined extracts were washed with aqueous sodium metabisulphite (10% w/w, 2×300 ml), dried over magnesium sulphate, and the solvent removed by evaporation. The residue was triturated with petroleum ether (b.p. 40°-60° ) and the solid collected by filtration to give the novel compound 4'-methoxy-3'-methyl-N-methylacetanilide, m.p. 65°-66°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[F:31][C:32]([F:47])([F:46])[CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[C:37]([CH2:44]O)[CH:38]=[CH:39][CH:40]=2)[CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:17]=[C:15]1[N:14]([CH2:44][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:36]=2[CH2:35][N:34]([CH2:33][C:32]([F:47])([F:31])[F:46])[CH2:43][CH2:42]3)[C:13]2[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:20]3[S:24][N:23]=[CH:22][N:21]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[O:16]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Reactant: OCc1cccc2c1CN(CC(F)(F)F)CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)ccc2n1Cc1cccc2c1CN(CC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (16.5 mg, 0.037 mmol) and 7-5 (9.02 mg, 0.037 mmol) in THF (368 μl) at RT was treated with PS-bound triphenylphosphine (1.84 mmol/g, 40.2 mg, 0.074 mmol), and DTBAD (16.94 mg, 0.074 mmol). After 30 min, LCMS showed complete consumption of SM. Filtered through Celite and concentrated in vacuo. Dissolved in 245 uL DCM, 123 uL TFA and stirred at RT. After 30 min, diluted with 1 mL MeOH, filtered through Celite and washed with 1 mL MeOH. Concentrated in vacuo and purified by reverse-phase HPLC (C18 column, 5-70% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 7-6 as an off-white solid. 1H NMR δ (ppm) (DMSO-d6): 8.48 (1H, s), 7.78 (1H, d, J=1.69 Hz), 7.67 (1H, dd, J=8.28, 1.72 Hz), 7.25 (1H, d, J=8.33 Hz), 7.14-7.09 (2H, m), 6.92 (1H, d, J=6.83 Hz), 5.00 (2H, s), 3.99 (3H, s), 3.54 (3H, d, J=12.20 Hz), 2.90 (2H, s). HRMS C21H19F3N5O4S2 [M+H] calc 526.0825, obs. 526.0806.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:21]([N:20]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:4][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:25])[CH2:23][CH3:24])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CNS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To a solution of {5-[3-(4-aminomethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (60 mg, 168 μmol) and DIPEA (33 mg, 252 μmol) in DCM (10 mL), methanesulfonyl chloride (23 mg, 202 μmol) is added. The mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM, the organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined and concentrated. The product is dissolved in methanol and filtered over Amberlyst A21. The filtrate is evaporated and dried to give the title compound (10 mg) as a colourless resin; LC-MS: tR=0.52 min; [M+1]+=435.03; 1H NMR (CDCl3): δ1.14 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 2.68 (q, J=6.8 Hz, 4H), 2.93 (s, 3H), 3.79 (s, 2H), 4.42 (d, J=5.8 Hz, 2H), 5.04-5.10 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.68 (s, 1H), 8.15 (d, J=8.3 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[C:15]([C:16]([O:18]C)=O)=[CH:14][S:13][CH:12]=1)=[O:9].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.NC1C(C(OC)=O)=CSC=1.BrCCCCCN=C=O>C1(C)C=CC=CC=1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[C:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:16](=[O:18])[C:15]4=[CH:14][S:13][CH:12]=[C:11]4[NH:10][C:8]3=[O:9])[CH2:30][CH2:29]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCCBr
Agent: COC(=O)c1cscc1N
Agent: O=C=NCCCCCBr
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 98 %

Procedure:
The title compound was prepared by the procedure of Example 10 using N-(5-bromopentyl)-N'-(4-carbomethoxythien-3-yl)urea (9.01 g, 26 mmol) and 4-[bis(4-fluorophenyl)methylene]piperidine (14.76 g, 52 mmol). The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with one equivalent of 5-bromopentylisocyanate in toluene at room temperature for four hours to produce the urea as a tan solid (98% yield). This material was recrystallized from CH2Cl2 /ether/hexane to afford the urea as a white solid, mp 92°-93.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[C:34]([CH3:39])([CH3:38])[CH2:33][C:32]3([CH3:41])[CH3:40])O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:37]3[CH:36]=[C:35]4[C:31](=[CH:30][CH:29]=3)[C:32]([CH3:41])([CH3:40])[CH2:33][C:34]4([CH3:39])[CH3:38])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 4,4,5,5-tetramethyl-2-(1,1,3,3-tetramethylindan-5-yl)-1,3,2-dioxaborolane.