Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[CH:19]1[CH:24]=[N:23][CH:22]=[C:21]([N:25]=[C:26]=[S:27])[CH:20]=1>O1CCOCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:26]([NH:25][C:21]3[CH:22]=[N:23][CH:24]=[CH:19][CH:20]=3)=[S:27])[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: S=C=Nc1cccnc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=S)Nc3cccnc3)nc12
Temperature: 100 °C

Procedure:
To a stirred solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (80 mg, 0.3 mmol) in dioxane (3 ml) was added pyridine-3-isothiocyanate (64 mg, 0.47 mmol) and the mixture heated to 100° C. for 69 h. After cooling to r.t. the resulting yellow suspension was filtered, washed with ether (5 ml) and dried under vacuum (0.05 mmHg, 50° C., to afford the title compound as a; light yellow solid (98 mg, 80% yield), MS: m/e=393.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1.[Li+].[OH-].C([O-])(=[O:18])C.[NH4+].[Cl-]>C(OC(=O)C)(=O)C.CO.C(Cl)(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH2:10][OH:18])=[N:7][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cnc(CO)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 3 h

Procedure:
5-Methoxy-2-methyl-4-nitropyridine 1-oxide (7 g, 0.038 mol) was dissolved in acetic anhydride (70 mL, Sdfine, India) and the resulting solution was stirred for 3 h at 150° C. The reaction mixture was concentrated and Et2O (250 mL) was added to the residue and it was neutralized with sat'd NaHCO3 (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate, concentrated to afford a pale yellow solid which was dissolved in MeOH and THF (100 mL) and treated with LiOH (2.73 g, 0.113 mol). The reaction mixture was stirred for 2 h at rt. The progress of the reaction was monitored by TLC (5% MeOH in CHCl3). After completion of acetate hydrolysis, sat NH4Cl (20 mL) was added and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (s, 1H), 7.81 (s, 1H), 5.62 (t, J=5.7 Hz, 1H), 4.59 (d, J=6 Hz, 2H), 4.04 (s, 3H). MS (ESI, positive ion) m/z: 185.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:7]=2)(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[C:1]([C:4]1[N:5]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[Cl:21])[C:6]2[C:11]([C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:7]=2)(=[O:3])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1ccc2c(CC(C)C)c(C(C)=O)[nH]c2c1
Product: COC(=O)c1ccc2c(CC(C)C)c(C(C)=O)n(Cc3ccccc3Cl)c2c1

Procedure:
Methyl 2-acetyl-1-(2-chlorobenzyl)-3-isobutylindole-6-carboxylate (71.4 mg) was prepared from methyl 2-acetyl-3-isobutylindole-6-carboxylate (58 mg) and 2-chlorobenzyl bromide (0.04 ml) in a similar manner to that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[SH:11][CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)NC(Nc1c(Cl)cccc1Cl)=[SH]CC(C)C
Yield: 92 %

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 2.1 g (0.015M) of ground potassium carbonate, 3.3 ml (0.03M) of isobutylbromide and 50 ml of acetone were heated together under stirring and reflux for 4 hours. The acetone was then distilled off. The residue in the flask was washed with water and then filtered. 5.9 g (92% of theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-isobutyl-thiourea melting at 106° to 112° were obtained. After recrystallization from benzene the product melted at 114° to 116° C.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[NH3:23]>CCCCCC>[NH2:23][SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: N
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 41 h
Yield: 88 %

Procedure:
In an argon atmosphere, 5.42 g (15.7 mmol) of Si(tOctNCHCHNtOct)(H)Cl was dissolved in 20 mL of hexane. The resulting solution was deaerated by Freeze-Pump-Thaw cycling and after creating an ammonia atmosphere in the reaction vessel by connecting thereto a balloon having an internal volume of 5 L and being filled with ammonia, the solution was stirred at room temperature for 41 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 115° C./1.2×102 Pa) to obtain 2-amino-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NH2) as a pale yellow liquid (yielded amount: 4.52 g, yield: 88%). The thus-obtained Si(tOctNCHCHNtOct)(H)NH2 was measured for the 1H and 13C NMR spectra, as a result, these spectra agreed with spectra of that obtained in Example-24.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH:35](NC1N=C(C(O)=O)C=C(C)N=1)(C)C.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH:32]([NH:31][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)([CH3:33])[CH3:35]
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(NC(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.92 min, [M+H]+=471.25.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:13]([C:12]1[CH:18]=[CH:19][C:9]([C:6]#[C:7][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Ethynylbenzaldehyde (10 g) obtained by the same method as the synthesis method described in the literature (Tetrahedron Letters, 2007, Vol. 48(33), pp. 5817-5820), PdCl2(PPh3)2 (3.4 g), CuI (1.5 g), and triethylamine (32 mL) were added to a THF (0.25 L) solution of ethyl 4-iodobenzoate (20 g). The mixture was stirred for 3 hours at room temperature, and the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/chloroform=80/20→0/100) to obtain ethyl 4-[(4-formylphenyl)ethynyl]benzoate (yellow solid) (16 g, 69%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:23]12[NH:31][CH:27]([CH2:28][O:29][CH2:30]1)[CH2:26][O:25][CH2:24]2.[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH:27]12[N:31]([C:3]3[C:2]([Br:1])=[CH:21][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=4)=[O:8])=[CH:5][N:4]=3)[CH:23]([CH2:30][O:29][CH2:28]1)[CH2:24][O:25][CH2:26]2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: C1OCC2COCC1N2
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(Br)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 55.4 mg, 0.14 mmol) and 3,7-Dioxa-9-aza-bicyclo[3.3.1]nonane (Organic Chemistry (2006), 71(1), 413-415) (24.53 mg, 0.14 mmol) were dissolved in DMF (150 μL). KF (24.4 mg, 0.42 mmol) was added and the RM mixture was stirred at 140° C. for 18 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc from 20% to 60% EtOAc) to afford the title compound as a white solid. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=490.1 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][CH2:9]C1=O.[OH-:19].[Na+].O>C1COCC1.C(OCC)(=O)C>[OH:7][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][OH:19]
Reactant: [OH-]
Reactant: O=C1CC=Cc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCc1ccccc1O
Reaction time: 4 h

Procedure:
To 20 g of lithium aluminum hydride in 200 ml of THF at 0° C. is added dropwise 84 g of 1-benzoxepin-2-one in 200 ml of THF. After addition is complete the reaction mixture is allowed to come to room temperature and stirred 11/4 hours. The reaction 5% of NaOH and 60 ml H2O are sequentially added. The mixture is then diluted with ethyl acetate, acidified and filtered through celite. The EtOAc layer is separated, dried (MgSO4) and concentrated to obtain 3-(-o-hydroxyphenyl)-1-propanol as a brown oil which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24]>>[CH2:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)[CH3:24]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: CN(c1cccc(-c2csc3cnc(Cl)nc23)c1)S(C)(=O)=O
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cccc(N(C)S(C)(=O)=O)c5)c4n3)cn2)CC1
Yield: 42.7 %

Procedure:
N-(3-(2-(6-(4-Ethylpiperazin-1-yl)pyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)-N-methylmethanesulfonamide (19 mg, 64% yield) was prepared in the same manner as Step 10 of Example 1 using N-(3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)-N-methylmethanesulfonamide (20 mg, 0.57 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (18 mg, 0.085 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([N:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[CH:14]=[C:13]([N+:23]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.CCO>CO.C1COCC1.[Pt]>[NH2:23][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])=[O:10])[C:19]2[N:18]=[C:17]([N:20]([CH3:21])[CH3:22])[NH:16][C:15]=2[CH:14]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N(C)C)nc12
Agent: [Pt]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a suspension of N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-nitro-1H-benzimidazole-4-carboxamide (580 mg) in MeOH-THF (1:1, 60 mL), was added 2N hydrogen chloride/EtOH (1 mL). To the mixture was added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (150 mg) and it was stirred vigorously under hydrogen atmosphere (0.2 MPa) for 3 hours. The reaction mixture was filtered off through celite, and the mother liquid was concentrated. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (265 mg) as brown powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][CH:46]=[C:45]([CH3:49])[N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][CH:46]=[C:45]([CH3:49])[N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cncc(-c2cc(C)c(Br)c(C)c2)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-6-methyl-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 26): tR=0.93 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 64 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 64%). MS (m/e): 532.0 (M+H+, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:20])[CH2:18][CH3:19]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:22]([O:21][C:17](=[O:20])[CH2:18][CH3:19])[C:23](=[O:24])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CCC(=O)ONC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)ON(C(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
Benzyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (51) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(benzyloxy)carbonyl]-amino propanoate according to Scheme 2. (0.56 g, 50%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (1H, d, 7.9 Hz), 8.35 (1H, d, 7.9 Hz), 7.80-7.86 (1H, m), 7.68-7.73 (1H, m), 7.30-7.39 (3H, m), 7.18-7.23 (2H, m), 5.17 (2H, br. s.), 3.30 (3H, s), 2.58 (2H, br. s.), 1.23 (3 H, t, 7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:24][CH2:23][CH2:22][N:21]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NCCCN
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NCCCN12
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (17 g), 1,3-diaminopropane (25 mL), and toluene (125 mL) was heated at reflux for 19 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water, and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (26 g) as a solid, m.p. 126-128° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cn2)CC1
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a stiffed solution of 2,5-dibromopyridine (10 g, 42.19 mmol, 1.00 equiv) in toluene (1000 mL) under nitrogen at −78° C. was added dropwise n-BuLi (18 mL, 2.5 M in toluene). After 1 h at −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.25 mmol, 1.19 equiv) in toluene (200 mL) was added dropwise while stirring. After an additional 2 h of stirring at −78° C., the reaction was then carefully quenched by the addition of 300 mL of water. The resulting mixture was extracted with 3×500 mL of ethyl acetate. The combined organic layers were washed with 1×300 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) to yield 6.5 g (42%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)O1>>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccsc2)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Product: c1nc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3ccsc3)n2n1

Procedure:
This compound may be prepared using methods as described for Compound 120, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)amine and 4,4,5,5-tetramethyl-2-thiophen-3-yl-[1,3,2]dioxaborolane in step 4. LCMS: Rt 1.19 min (95%), m/z (ESI) 379 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)OC(C)O2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)O2
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
59.3 g of 2-methyl-5-acetamino-1,3-benzodioxole were nitrated at 15°-25° C. in 225 ml of glacial acetic acid by the dropwise addition of 27 ml of nitric acid in 95 ml of glacial acetic acid. After 30 minutes, the temperature rose spontaneously to 45° C. and the color of the mixture changed from yellow to red. The precipitated crystals were removed by filtration under suction and washed with methanol. There were obtained 64.4 g (88.5% of theory) of 2-methyl-5-acetamino-6-nitro-1,3-benzodioxole of melting point 112°-113° C.
Reaction SMILES: C(OC([C:11]1([NH2:25])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:12]1=[O:24])=O)C1C=CC=CC=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:25][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[C:12]1=[O:24]
Reactant: N#Cc1ccc(N2CCC(N)(C(=O)OCc3ccccc3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(N2CCC(N)C2=O)cc1
Reaction time: 0.67 h
Yield: 80 %

Procedure:
50 g (0.15 mol) of 3-benzyloxycarbonyl-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine are suspended in 600 ml of methanol, and 14.1 ml of 36% hydrochloric acid are added. After the addition of 2.5 g of 5% palladium on activated carbon, hydrogen is passed through at 45° C. After 40 minutes, the mixture is cooled, the catalyst is filtered off and the filtrate is concentrated to dryness. Recrystallisation from methanol/isopropanol yields 28.5 g (80%) of 3-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=O)=[CH:10]2)(=[O:5])=[O:4].C[O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:1][C:2]([F:20])([F:19])[S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([OH:31])=[O:22])=[CH:25][CH:26]=1)=[O:18])=[CH:10]2)(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2[nH]1
Product: O=C(O)c1ccc(NC(=O)c2cc3cc(NS(=O)(=O)C(F)(F)F)ccc3[nH]2)cc1

Procedure:
Same procedure as Example 82 except 5-Trifluoromethansulfonylamino-1H-Indole-2-Carboxylic Acid and 4-aminobenzoic methyl ester was used. 1H-NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H, COOH), 11.99 (d, J=1.2 Hz, 1H, NHCO), 11.61 (s, 1H, SNH), 10.54 (s, 1H, NH-1), 7.95 (m, 4H, ArH), 7.61 (d, J=2.1 Hz, 1H H-4), 7.50 (m, 2H, H-7 & H-3), 7.14 (dd, J=2, 9 Hz, 1H, H-6), MS m/z 426 (M−H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][S:15](=[O:16])[C:11]=3[CH:10]=2)=[O:8])=[CH:5][CH:4]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[CH:14][S:15](=[O:16])[C:11]=3[CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)S(=O)C=N3)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)c1ccc2c(c1)S(=O)C=N2

Procedure:
0.02 mol of 6-(4-methoxybenzoyl)benzothiazolinone obtained in Example 30 are placed in a mixture of 15 cc of 47% hydrobromic acid and 15 cc of acetic acid. The mixture is refluxed with agitation for 72 hours. It is allowed to cool and the product is drained, dried, washed with water, and recrystallized from alcohol at 95° C.