Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]([N:10]([CH2:12][C:13]#[C:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1)[OH:11])=[O:9])C1C=CC=CC=1.[NH3:35]>CO>[OH:11][N:10]([CH2:12][C:13]#[C:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:16]=1)[C:8]([NH2:35])=[O:9]
Reactant: N
Reactant: COc1ccc(-n2nc(C#CCN(O)C(=O)Oc3ccccc3)cc2-c2ccc(C)cc2)cc1
Solvent: CO
Product: COc1ccc(-n2nc(C#CCN(O)C(N)=O)cc2-c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
Alternatively, N-phenoxycarbonyl-N-(1-(1-(4-methoxyphenyl)-5-(4-methylphenyl)-3-pyrazolyl)-1-propyn-3-yl)hydroxylamine (4.67 mmol, 2.12 g) was dissolved in 20 mL of 14% w/w solution of ammonia in MeOH and stirred overnight in a stoppered round-bottomed flask. The solution was concentrated to give 2.2 g of orange oil which was purified by MPLC to give 0.89 g (51%) of Cpd. 1 as an off white solid. Tables I & J list the analytical data for Cpd. 1 as well as other compounds which were prepared in this manner.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]1=2)[CH3:26]
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 2.5 h
Yield: 95 %

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (520 mg, 2.22 mmol), cesium carbonate (1.52 g, 4.7 mmol), iodoethane (355 uL, 4.44 mmol) and DMF (12 mL). Stirred at room temp. for 2.5 hours. Evaporated off solvent, added water and extracted into methylene chloride. Dried organic layer over sodium sulfate, filtered and concentrated under reduced pressure to yield a brown solid, 1-Ethyl-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (553 mg, 95%). mp 67° C.; LCMS: m/z=263.08 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H, J=2.5 Hz), 8.17 (dd, 1H, J=8.7, 2.6 Hz), 7.38 (d, 1H, J=8.8 Hz), 3.89 (m, 2H), 2.31 (m, 2H), 2.12 (m, 2H), 1.42 (s, 6H), 1.33 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[S:17](Cl)([CH3:19])=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.Cl>[CH3:19][S:17](=[N:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14])([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N=S(C)(=O)Cl)cc1
Reactant: C1CCNC1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N=S(C)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (1.53 mL) is added drop wise to N-(4-methylbenzenesulfonyl)methylsulfonimidoyl chloride (5.00 g) in dichloromethane (10 mL) at 0° C. and the resulting mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with dichloromethane, hydrochloric acid (1 N; 10 mL) is added, and the mixture is stirred for 0.5 h at room temperature. The organic phase is separated, washed with aqueous NaHCO3 solution and water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 100: 080:20) to give the title compound. LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=303 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].O1CCCC1.[NH3:33]>>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH2:33])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)OC)n1
Reactant: N
Solvent: C1CCOC1
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(N)=O)n1
Reaction time: 27 h

Procedure:
To a suspension of methyl 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylate (125 mg) in ammonia (Ca. 7 mol/L methanol solution, 20.1 mL) was added tetrahydrofuran (6.7 mL) at room temperature, followed by stirring for 27 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (120 mg). 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=7.5 Hz), 1.25 (3H, d, J=6.9 Hz), 1.45-1.80 (2H, m), 2.65-2.80 (1H, m), 3.93 (3H, s), 5.39 (2H, s), 5.45-5.65 (1H, br), 6.30 (1H, s), 6.65-6.75 (1H, m), 7.11 (1H, s), 7.19 (1H, s), 7.60-7.80 (2H, m), 8.00-8.15 (1H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:18]([CH2:26][CH2:27][CH3:28])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[N:31](CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC)C(=O)C>>[NH2:31][C:13]1[C:12]2[N:17]=[C:18]([CH2:26][CH2:27][CH3:28])[N:19]([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]=2[N:14]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Reactant: CCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O

Procedure:
The general method described in Part G of Example 6 was followed using 5-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (1.0 g, 2.69 mmol) in lieu of N-methoxy-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide. Recrystallization from hot methanol and water afforded 0.1815 g of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as a tan powder, mp 202-204° C. MS (APCI) m/z 387.1 (M+H+); Anal. calcd for C24H26N4O 0.66H2O: C, 72.36; H, 6.91; N, 14.06. Found: C, 64.95; H, 7.78; N, 17.92.C24H26N4O 0.66H2O Exact Mass: Theor. Mass: 387.2185 Da. Meas. Mass: 387.2191 Da. Mass Dev. 1.5 ppm.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][CH:20]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][CH:20]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSC1=C([N+](=O)[O-])CC(CCc2ccccc2)CN1
Product: N=C(N)Nc1nc(CSCCNC2=C([N+](=O)[O-])CC(CCc3ccccc3)CN2)cs1

Procedure:
The title compound is prepared from 2-(2-guanidino-4-thiazolylmethylthio)ethylamine and 2-methylthio-3-nitro-5-(2-phenylethyl)-1,4,5,6-tetrahydropyridine by a process analogous to that given in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][NH:16][CH:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=2)[CH:27]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C@@H:18]([CH3:19])[CH2:17][N:16]([CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=5)[CH:27]=4)[C@@H:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: Clc1ccc2cc(CBr)ccc2c1
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)[C@@H](C)CN1Cc1ccc2cc(Cl)ccc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 268, using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one, EXAMPLE 87, and 2-bromomethyl-6-chloronaphthalene, EXAMPLE 12. 1H NMR (CDCl3, 300 MHz) δ8.59 (s, 1H), 7.79 (d, 1H), 7.70-7.12 (m, 3H), 7.68-7.67 (m, 2H), 7.55 (d, 1H), 7.39 (d, 1H), 4.78 (d, 2H), 3.98 (d, 2H), 3.44 (s, 3H), 3.38 (t, 1H), 2.64 (m, 2H), 1.26 (d, 3H). MS (ISP) 490, 492, (M+H), Cl pattern.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[I:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[OH:41]>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:39])[F:40])=[CH:36][C:31]=1[I:30])#[N:2]
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
Prepared according to Method O (below) at room temperature using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68) and 2-iodo-4-(trifluoromethyl)phenol (Preparation 224). The title compound was isolated as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]=1.CO.O.[NH2:25]N>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([NH:3][NH2:25])[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1
Reactant: NN
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.67 h

Procedure:
To a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol is added 1.25 parts of 80% hydrazine hydrate. The suspension is stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Melting point: around 170° C (browning), 202° C to 204° C (decomposition).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:2][CH3:3].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:14][S:15]([C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C(N)=O
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chlorosulphonic acid (200 ml.), cooled to 10° C., was treated with 2-propoxybenzamide (60 g.) in aliquots with stirring during 45 minutes. When complete solution had occurred, the solution was allowed to stand at room temperature for 24 hours. The resulting yellow-brown solution was then added dropwise, with stirring, to ice (1.5 kg.), keeping the temperature at or below 0° C. The precipitated solid was filtered off, washed with ice-cold water, and sucked dry. The solid was then dissolved in dichloromethane (approximately 2 liters), any water still present was separated off, and the organic layer was dried over calcium chloride and then over magnesium sulphate. Most of the dichloromethane was removed in vacuo, the low volume residue was treated with petroleum ether (b.p. 40° - 60° C.) and the precipitated solid was filtered off, to give crude 5-chlorosulphonyl-2-propoxybenzamide (81 g.), m.p. 122° - 129° C.
Reaction SMILES: [CH:1]1([CH:6]2[C:11]([O:12][CH3:13])=[CH:10][CH2:9][CH:8]=[C:7]2[O:14]C)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[CH:1]1([CH:6]2[C:11]([O:12][CH3:13])=[CH:10][CH2:9][CH2:8][C:7]2=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC1=CCC=C(OC)C1C1CCCC1
Agent: Cl
Solvent: CO
Product: COC1=CCCC(=O)C1C1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a solution of 2-cyclopentyl-2,5-dihydro-1,3dimethoxybenzene (5 g, 27 mmol) in methanol (50 mL) was added 2.5% hydrochloric acid (10 mL) dropwise at 0° C. The reaction mixture was stirred for 45 minutes and diluted with 30 mL of ice-cold water. The product was extracted with ether (3×100 mL). The combined organic extract was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo yielded the title compound as light yellow oil (4.3 g, 94.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[CH:7]1([CH2:6][O:5][C:4]2[CH:3]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1cccc(OCC2CCCCCC2)c1
Reactant: C=CCNC(=O)C(F)(F)F
Product: O=C(NC/C=C/c1cccc(OCC2CCCCCC2)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
((3-Bromophenoxy)methyl)cycloheptane was coupled with N-allyl-2,2,2-trifluoroacetamide following the method used in Example 10 except that the mixture was heated for 23 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and water. The combined organics were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (10% EtOAc-hexanes) gave (E)-N-(3-(3-(cycloheptylmethoxy)phenyl)allyl)-2,2,2-trifluoroacetamide. Yield (0.7015 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=7.6 Hz, 1H), 6.90-6.94 (m, 2H), 6.81 (dd, J=8.4, 1.6 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.39 (br s, 1H), 6.12-6.19 (m, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.73 (d, J=9.6 Hz, 2H), 1.92-2.10 (m, 1H), 1.82-1.90 (m, 2H), 1.42-1.76 (m, 8H), 1.24-1.36 (m, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[2-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 222) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.70-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 7H), 4.75-4.95 (m, 1H), 6.10 (brs, 1H), 6.50-7.40 (m, 8H), 7.65-7.80 (m, 4H), 9.48 (s, 1H), 10.42 (s, 1H); MS (ES) m/z: 525.6 (MH+); HRMS Calcd. for C27H33N4O5S(MH+): 525.2172. Found: 525.2164.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(O)C>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: NC1CCC(F)(F)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Yield: 61.2 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 200 mg, 0.954 mmol), 4,4-difluorocyclohexanamine (491 mg, 2.86 mmol) and DIPEA (367 mg, 2.86 mmol) in iPrOH (2 mL) was heated in a sealed tube at 80° C. for 2 h. Then the reaction mixture was quenched with water at rt and was extracted with CHCl3. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography using 3-5% EtOAc in CHCl3 to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.59-8.55 (m, 2H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.27-8.25 (d, J=7.8 Hz, 1H), 7.69-7.63 (t, J=7.8 Hz, 1H), 4.41 (m, 1H), 2.26-2.00 (m, 6H), 1.75-1.71 (m, 2H); MS (m/z): 309.18 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][NH:28][CH2:29][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:31][N:32]([CH3:39])[CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][N:28]([C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][N:32]([CH3:39])[CH3:31])[CH2:29][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CNC5)cc2Cl)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 29A (46 mg, 0.11 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (25 mg, 0.15 mmol) to yield 19 mg (33%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH2:15][N+:16]([O-])=O)[CH2:11][N+:12]([O-])=O)[CH:5]=1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([CH2:15][NH2:16])[CH2:11][NH2:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])CC(C[N+](=O)[O-])c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NCC(CN)c1cccc(N)c1

Procedure:
A mixture of 1-nitro-3-[2-nitro-1-(nitromethyl)ethyl]benzene (115 mg, 0.45 mmol) and 58 mg platinum (IV) oxide in 6 mL MeOH contained in a pressure tube was reacted under 65 PSI hydrogen. After 16 hours the mixture was filtered and rinsed with MeOH. The MeOH solution of product was stored under N2 in the freezer and used as is for the next reaction [upon evaporation of MeOH solvent 69.9 mg (94%) of the title compound was obtained as a light yellow oil]. 1H NMR (CD3OD) δ: 7.06-7.13 (m, 1H), 6.55-6.65 (m, 3H), 2.83-2.91 (m, 2H), 2.72-2.81 (m, 2H), 2.57-2.68 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Br)ccc1O
Yield: 61.6 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:5]([S:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:4])=[O:3])[CH:6]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1.0 g, 3.3 mmol, Buttpark Ltd.) in dichloromethane (10 mL) was added N-ethyldiisopropylamine (854 mg, 1.15 mL, 6.61 mmol) and morpholine (317 mg, 317 μL, 3.63 mmol). The reaction mixture was stirred at room temperature for 2 hours, poured on 10% aqueous sodium bicarbonate solution (100 mL) and dichloromethane (100 mL) and the layers were separated. The aqueous layer was extracted a second time with dichloromethane (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 35:65). Off-white solid (1.04 g, 89%). MS (EI): m/z=353.087 ([M]).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)C>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.6 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) in N,N-dimethylformamide (1.0 ml) was added phenylacetyl isothiocyanate (42 mg), followed by stirring at room temperature for 22 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to give a solid, which was suspended in diethyl ether. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (22 mg, 0.043 mmol, 29%) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=O)=[CH:4][CH:3]=1.[NH:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH2:21]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:21][NH:20][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: Cn1nnc2ccc(C(=NNC(=O)OC(C)(C)C)c3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 59.1 %

Procedure:
A mixture of 27.17 g of (4-chlorophenyl)(1-methyl-1H-benzotriazole-6-yl)methanone, 14.24 g of 1,1-dimethylethyl hydrazinecarboxylate and 80 ml of ethanol was stirred for 21 hours at reflux temperature. The reaction mixture was cooled to room temperature and stirring was continued for 2 hours. The precipitate was filtered off, washed with ethanol and dried in vacuo at 50° C., yielding 22.8 g (59.2%) of 1,1-dimethylethyl [(4-chlorophenyl)(1 -methyl-1H-benzotriazol-6-yl)-methylene]hydrazine carboxylate (interm. 1-b).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([C:10](=[O:13])[CH2:11][F:12])=[N:6][C:7]=1[O:8][CH3:9].[CH3:22][N:23]([CH:25](N(C)C)OC(C)(C)C)[CH3:24]>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:25])[CH:24]=[C:11]([F:12])[C:10]([C:5]1[C:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:3][C:2]([F:1])=[C:7]([O:8][CH3:9])[N:6]=1)=[O:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1nc(C(=O)CF)c(NC(=O)OC(C)(C)C)cc1F
Solvent: Cc1ccccc1
Product: COc1nc(C(=O)C(F)=CN(C)C)c(NC(=O)OC(C)(C)C)cc1F
Temperature: 40 °C
Yield: 48.8 %

Procedure:
A solution of 1,1-dimethylethyl [5-fluoro-2-(fluoroacetyl)-6-(methyloxy)-3-pyridinyl]carbamate (3.72 g, 12.32 mmol) in dry toluene (20 ml) was treated with {(dimethylamino)[(1,1-dimethylethyl)oxy]methyl}dimethylamine (Bredereck's reagent) (3.05 ml, 14.78 mmol) and heated at 40° C. for 2 hours. The mixture was evaporated and the residue triturated with 3×200 ml hexane and the remaining solid dried in vacuo to afford the product (2.15 g, 49%).