Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2([CH3:32])[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:5])=[O:4])=[N:24][CH2:23]2)[CH2:27][CH2:28]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CC2(C)CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.21 g), acetic anhydride (0.30 ml) and pyridine (6 ml) was stirred at 0° C. for 1 hr, and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.19 g, yield 84%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (6:1, volume ratio).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([O:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([NH:30][CH3:31])=[N:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([O-:17])=[O:16])[CH3:12].Cl[CH2:33]Cl>O>[CH2:11]([O:13][C@@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[S:29][C:28]([N:30]([CH3:31])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10])=[N:27][CH:26]=2)=[CH:23][CH:24]=1)[C:15]([O:17][CH3:33])=[O:16])[CH3:12]
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)[O-]
Reactant: CCCCCCCN=C=O
Reactant: ClCCl
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
0.17 ml (1 mmol) of heptyl isocyanate is added to a solution of 0.17 g (0.5 mmol) of 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propanoate in 10 ml of dichloromethane. The reaction medium is stirred at room temperature for 20 hours. The reaction medium is diluted with water and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 50/50 heptane/ethyl acetate mixture. 0.07 g (30%) of methyl 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylureido)thiazol-5-yl]phenyl}propanoate is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([F:26])[CH:22]=1)[CH2:18][C@H:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Temperature: 0 °C

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol (1 equiv) was dissolved in DCM with TEA (2 equiv) then cooled to 0° C. and treated with MsCl (1.25 equiv)while stirring. The reaction mixture was removed from the cold bath, brought to ambient temperature, then quenched with MeOH and concentrated. The residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL). The organics were dried and concentrated and chromatographed over silica gel. 1H NMR (CD3OD) δ 7.74 (d, J=2.0 Hz, 1H), 7.53 (dd, J=2.0, 8.7 Hz, 1H), 6.88 (m, 2H), 6.77 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.23-4.39 (m, 2H), 4.25 (br m, 1H), 4.12 (m, 1H), 3.87 (td, J=3.1, 7.8 Hz, 1H), 3.29 (dd, J=3.5, 13.9 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J=3.2, 12.7 Hz, 1H), 2.98 (dd, J=7.9, 12.6 Hz, 1H), 2.74 (dd, J=11.0, 13.9 Hz, 1H), 2.14 (br m, 2H). MS (ESI+) calcd for C20H23F2IN2O4S m/z 553.38 (M+H)+. Found 553.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([F:12])[S:7]1(=[O:14])=[O:13].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([F:36])([F:12])[S:7]1(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(CN2CCCC(F)S2(=O)=O)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCC(F)(F)S2(=O)=O)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6-fluoro-1,2-thiazinane-1,1-dioxide (0.500 g, 1.8 mmol) in anhydrous tetrahydrofuran (30 mL), cooled to −78° C., was slowly added 2.5 N n-butyl lithium in hexanes (1.262 mL, 3.2 mmol). The solution was stirred at −78° C. for 1 hr, a solution of N-fluorobenzene sulfonimide (1.243 g, 3.9 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added over 10 mins, and the mixture stirred at −78° C. for 3 hrs and at room temperature for 3 hrs. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (15-60% ethyl acetate/hexanes) to give a yellow oil (0.09 g). 1H NMR (CDCl3, 300 MHz) δ 7.25-7.21 (d, 1H, J=8.4 Hz), 6.50-6.47 (dd, 1H, J=2.4, 8.4 Hz), 6.45-6.44 (d, 1H, J=2.4 Hz), 4.43 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.38-3.37 (t, 2H, J=5.1 Hz), 2.58-2.45 (m, 2H), 2.00-1.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(30 mg, 57%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b) and 4-fluorophenylsulfonyl chloride (52.9 mg, 0.27 mmol); HRMS-FAB+ for C20H19N2O2SF2 calculated MH+ : 389.11353; found: 389.11544.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[O:24]>C(#N)C.O>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23](=[O:24])[CH2:22][NH:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(N2CC(=O)NS2(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CN(c2cccc(NCC(=O)c3ccc(Cl)cc3Cl)c2)S(=O)(=O)N1
Temperature: 35 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-(3-amino-phenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one (5 g, 22 mmol) in 37.5 mL of 9:1 v/v acetonitrile-water was added NaHCO3 (4.62 g, 55 mmol). The mixture was stirred at 25° C. while 2-bromo-1-(2,4-dichloro-phenyl)-ethanone (7.1 g, 26.4 mmol) was added. The mixture was stirred for 12-16 hours at 35° C. The mixture was cooled on an ice bath to further precipitate the product, which was then collected by filtration. The filtrate was concentrated under reduced pressure and a second crop of crude product was collected. The combined crude product was washed once with 25 mL water and dried, then washed once with 10 mL methyl tert-butyl ether and dried, to provide 6.36 g (70% yield) of 5-{3-[2-(2,4-dichloro-phenyl)-2-oxo-ethylamino]-phenyl}-1,1-dioxo-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([NH:15][C:16]2([S:22][CH3:23])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2].C(OO)(=[O:34])C>O1CCOCC1.C(O)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([NH:15][C:16]2([S:22]([CH3:23])=[O:34])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(SC)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Reactant: CC(=O)OO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The azetidinone (60) (250 mg) in dry dioxan (10 ml) was treated with a (5.07% w/v) solution of peracetic acid in acetic acid (0.69 ml) for 1.5 hour. The solvent was then evaporated in vacuo, the complete removal of acidic residues being ensured. Silica gel chromatography of the residue gave the title compound as a pale-white solid (149 mg), νmax. (Nujol) 3300, 1760, 1710, and 1670 cm-1, δ[(CD3)2SO] 0.65, 0.93, 1.16 and 1.19 (each d, J6.5 Hz, together 3H), 1.07 (t, J7 Hz, 3H), 1.99, 2.14, 2.39, 2.64 and 2.68 (each s, together 3H), 3.37 (q, J7 Hz, 2H), 3.47-3.52 (m, 2H), 3.79-3.92 (m, 2H), 3.92-4.10 (complex m, together 1H), [5.45-5.60 (complex m) and 5.86 (d, J7 Hz), together 1H], 7.27-7.55 (m, 5H), 8.63 and 8.74 br (each s, together 1H, exch), 9.14 and 9.35 br (each s, together 1H, exch.), and 9.65-10.00 (complex m, together 1H, exch).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[ClH:26]>CO.C(OCC)C.[Fe]>[ClH:26].[NH2:13][C:12]1[CH:11]=[CH:10][C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:8][C:7]=1[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc(N)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.1 g (7.2 mmol) of methyl 3-(3-cyclopentoxy-4-nitrophenyl)-E-propenoate in 30 mL of methanol was added 6.3 mL (110.1 mmol) of glacial acetic acid and 2.0 g (35.8 mmol) of iron filings. The mixture was warmed to reflux and stirred for 16 hours after which time it was cooled to room temperature, filtered over Celite 545, and concentrated. Liquid chromatography over 200 g of silica gel using 50% ethyl acetate in hexane provided a pure oil. The product was dissolved in anhydrous ethyl ether, subjected to a stream of anhydrous hydrogen chloride gas upon which time an analytically pure, hydrochloride solid formed. The desired solid was collected, washed several times with anhydrous ethyl ether, and dried in vacuo.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9]C(=O)C)(=O)C.[OH-:13].[Na+].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:8][CH:7]=[CH:6][CH2:5][O:4][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:22])=[O:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC=CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.0 g (58.1 mmol) of 1,4-diacetoxy-2-butene (trans/cis=85/15), 100 mL of toluene, and 50 mL of a 50% sodium hydroxide aqueous solution were added into a four-necked flask (300 mL), and thereafter, 0.936 g (2.90 mmol) of tetra-n-butylammonium bromide was added thereto as a phase-transfer catalyst. The obtained mixture was stirred at room temperature for 1 hour, and 27.7 g (145 mmol) of 4-toluenesulfonyl chloride was then added to the reaction solution. The obtained mixture was stirred at room temperature for 2.5 hours, and 100 mL of water and 50 mL of toluene were then added to the reaction solution to facilitate liquid separation. The mixture was stirred, and an organic layer was then separated. The organic layer was washed with 100 mL of water three times, and the resultant was then filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 24.8 g of 1,4-di-4-toluenesulfonyloxy-2-butene in the form of a crude product of a light yellow solid (yield: 108%).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:9]=1)([CH3:6])[C:3](O)=[O:4].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][C:45]1[S:46][C:47]([Cl:50])=[CH:48][N:49]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:50][C:47]1[S:46][C:45]([NH:44][C:3](=[O:4])[C:2]([CH3:6])([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=3)[CH:9]=2)[CH3:1])=[N:49][CH:48]=1
Reactant: CC(C)(Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Reactant: Nc1ncc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1)C(=O)Nc1ncc(Cl)s1
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a solution of 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid (0.075 g, 0.204 mmol) in DCM (5 ml) added triethyl amine (0.034 ml, 0.24 mmol) and HOBt (0.0.037 g, 0.24 mmol) at 0° C. After stirring at this temperature for 5 min. added 2-amino-5-chlorothiazole (0.041 g, 0.285 mmol) and followed by EDCI (0.047 g, 0.244 mmol). The resulting solution was stirred for 12 h. then quenched with sat NH4Cl solution (15 ml). The aqueous phase was extracted with CH2Cl2 (3×50 ml). The organic phase were successively washed with 2% HCl (50 ml), brine (50 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:5 ethyl acetate:hexanes) to give N-(5-Chloro-thiazol-2-yl)-2-methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionamide (0.03 g, 30%). 1H NMR (400 MHz, CDCl3): δ 1.59 (s, 6H), 2.96 (t, J=6.8 Hz, 2H), 3.39 (bs, 2H), 3.7 (bs, 1H), 6.18 (s, 1H), 6.26-6.38 (m, 2H), 7.07 (m, 1H), 7.31 (m, 2H), 7.58 (d, J=8 Hz, 2H), 10.0 (s, 1H), MS (EI) m/z: 484.1 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][CH2:13][CH:12]([OH:15])[CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:15][CH:12]1[CH2:13][O:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of about 19.63 g of about 50% sodium hydride in about 450 ml of dimethylformamide was added, portionwise, over about 15 minutes about 67 g of 2-phenyl-m-dioxan-5-ol. After stirring about 20 minutes, the mixture was cooled in ice and about 69.95 g of benzyl bromide was added dropwise over about 20 minutes. The mixture was stirred at room temperature overnight, water was added and the solid collected. This solid was dissolved in hot toluene, dried, filtered and diluted with an equal volume of petroleum ether. After standing about 4 hours at about 0° C. the solid was collected, giving about 90.5 g of the desired title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][Cl:9])[N:5]([NH2:10])[C:4]=1[CH3:11].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl-:9].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:2][N+:3]2[CH:7]=[C:6]([CH2:8][Cl:9])[N:5]([N:10]=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:13]([CH3:22])[CH3:12])=[CH:15][CH:16]=3)[C:4]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(N)c(CCl)c[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)c(CCl)c[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 36 h

Procedure:
0.985 g (5 mmol) of 1,3-diamino-4-(chloromethyl)-2-methylimidazolium chloride and 7.45 g (50 mmol) of 4-dimethylaminobenzaldehyde are dissolved in 250 ml of glacial acetic acid. The solution is left to stand at room temperature for 36 hours and evaporated. The residue is placed on a column loaded with 150 g of silica gel (particle size 0.063-0.2 mm) and the product is eluted with chloroform/methanol (9:1). The eluate is evaporated and the product is crystallized from ethanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-4-(chloromethyl)-2-methylimidazolium chloride of melting point 188° (dec.)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:13])(=[O:24])(=[O:23])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CCO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CCOS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
The product of example 22 (a) (1.06 g, 5.6 mmol) was dissolved in CH2Cl2 (10 ml) and cooled in an ice bath while stirring under argon. Triethylamine (0.667 g, 6.6 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (0.687 g, 6 mmol). After 10 minutes the ice bath was removed and the mixture stirred at rt for 2 h. The solvent was stripped off and the title compound was isolated as a yellow oil. ES (+) MS m/e=268 (MH+), 290 (MNa+)
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([S:21](=[O:30])(=[O:29])[NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:13][CH:12]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][S:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9](=[O:10])[NH:8][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:12][CH:13]=2)(=[O:30])=[O:29])[CH2:28][CH2:27]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide hydrochloride F-2 (87 mg, 0.19 mmol) was dissolved and stirred in dichloromethane (2 mL). Triethylamine (58 mg, 0.08 mL, 0.57 mmol) was added followed by ethyl chloroformate (41 mg, 0.037 mL, 0.39 mmol). The reaction was stirred overnight at room temperature, then charged directly to a flash column. Elution with 99:1 dichloromethane:methanol afforded the titled compound the title compound as a white solid. Wt.: 60 mg (65%). 1H NMR (300 MHz, CDCl3) δ 8.59 (m, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.64 (m, 2H), 7.54 (d, 1H), 4.10 (m, 1H), 4.03 (q, 2H), 3.80 (m, 2), 3.64 (m, 1H), 3.18 (m, 1H), 2.68 (m, 2H), 2.12 (m, 2H), 1.79 (m, 2H), 1.68 (m, 1H), 1.58 (m, 2H), 1.47 (m, 2H), 1.24 (m, 6H), 1.18 (t, 3H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[NH:22][C:21]1=[O:28]>>[ClH:16].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[NH:22][C:21]3=[O:28])[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(F)ccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)[nH]c1=O
Product: COc1cc(F)ccc1N1CCN(CCCn2cc(C)c(=O)[nH]c2=O)CC1
Product: Cl

Procedure:
substituting 1-(4-fluoro-2-methoxyphenyl)piperazine and 1-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-{3-[4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 196°-197° C.; Anal.: Calcd. for C19H25FN4O3.(HCl)2 : C, 49.79; H, 6.16; N, 12.22%; Found: C, 50.13; H, 6.37; N, 12.27%;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](Cl)[N:3]=1.[OH-:11].[Na+].[CH3:13]O>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:11][CH3:13])[N:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: OCc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Product: COc1cc(CO)cc(Cl)n1
Yield: 28 %

Procedure:
A mixture of 2,6-dichloro-4-hydroxymethylpyridine (1.72 g, 16 mmol) and 40% aqueous sodium hydroxide solution (5 ml) in methanol (50 ml) was heated at reflux for 24 hours. The mixture was allowed to cool and the volatiles removed by evaporation. The residue was extracted with ethyl acetate and the solvent removed from the extracts by evaporation. The residue was recrystallised from ethyl acetate/hexane to give 2-chloro-4-hydroxymethyl-6-methoxypyridine (490 mg, 28%). 1H NMR Spectrum: (DMSOd6) 3.80(s, 3H); 4.45(d, 2H); 5.45(t, 1H); 6.70(s, 1H); 6.98(s, 1H)
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Br[CH2:22][CH2:23][F:24].CCN(C(C)C)C(C)C>CC#N>[F:24][CH2:23][CH2:22][NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1
Reactant: FCCBr
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FCCNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 82.5 %

Procedure:
Reference: For the preparation of the starting material compound 1, see Example 147. Into a 100-mL round-bottom flask, a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (250 mg, 0.87 mmol, 1.00 equiv) in CH3CN (15 mL) was added 1-bromo-2-fluoroethane (220 mg, 1.73 mmol, 2.00 equiv) and DIPEA (200 mg, 1.74 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 7 h at 70° C. in an oil bath. After completion, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (83%) of the desired 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a light yellow solid. MS (ES, m/z): 334 [M+H]+.