Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1
Yield: 100.6 %

Procedure:
By the method of Example 7, Step C, 75 g (0.40 mole) of 2-bromo-4-fluorotoluene, 70.6 g (0.40 mole) of N-bromosuccinimide, and 2.5 g (0.03 mole) of benzoyl peroxide were reacted in 450 ml of carbon tetrachloride, yielding 107.8 g of impure 2-bromo-4-fluorobenzyl bromide (68% assay).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:8](=[O:10])[CH2:7][CH2:6][CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)CCC1CC(=O)C1
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Product: CC(C)(C)c1ccc(NC(=O)CCC2CC(=O)C2)c([N+](=O)[O-])c1

Procedure:
reacting 3-(3-oxocyclobutyl)propanoic acid with 4-tert-butyl-2-nitroaniline to yield N-(4-tert-butyl-2-nitrophenyl)-3-(3-oxo-cyclobutyl)propanamide; and
Reaction SMILES: C1C=C2C(N(O)N=NC2=CC=1)=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:28]([C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])[C@@H:29]([C:42]([NH:44][C@H:45]([C:53]([OH:55])=O)[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[NH2:66][C@@H:67]([C:80]([NH:82][C@H:83]([C:91]([NH:93][CH2:94][C:95]([O:97][CH3:98])=[O:96])=[O:92])[CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74].S(O)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[NH:28]([C:56]([O:58][CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:57])[C@@H:29]([C:42]([NH:44][C@H:45]([C:53]([NH:66][C@@H:67]([C:80]([NH:82][C@H:83]([C:91]([NH:93][CH2:94][C:95]([O:97][CH3:98])=[O:96])=[O:92])[CH2:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([O:75][C:76]([CH3:78])([CH3:77])[CH3:79])=[O:74])=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.6 g of HOOBt, 1.3 g of NEM and 2.2 g of DCC are added to 5.3 g of Z-D-Lys(Boc)-Phe-OH and 6.4 g of H-D-Lys(Boc)-Phe-Gly-OMe, TosOH in 100 ml of DMF, with stirring. After the mixture has been left to stand overnight and the urea has been filtered off, the solvent is distilled off in vacuo. The residue is taken up in 300 ml of ethyl acetate/n-butanol (2:1), the mixture is washed, as above, with citric acid solution, sodium bicarbonate solution and water and dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is recrystallized from 60 ml of isopropanol.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]=[O:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:48])=[O:47]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C:32]([N:52]3[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]3)=[O:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1ncc(Nc2ncc(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared in an analogous manner to that described in Example 151 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinecarbaldehyde and 1-methanesulfonylpiperazine (Oakwood Products, West Columbia, S.C.), and the desired product 4-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((4-(methylsulfonyl)-1-piperazinyl)carbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine was isolated as a yellow solid (52% for two steps). 1H NMR (400 MHz, d6-DMSO) δ 12.11 (s, 1H) 8.85-8.93 (m, 1H) 8.45 (dd, J=2.15, 0.39 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H) 8.30-8.39 (m, 1H) 7.95 (br. s., 1H) 7.83 (br. s., 1H) 3.95 (s, 3H) 3.61-3.73 (m, 4H) 3.19 (t, 4H) 2.91 (s, 3H) 2.45 (s, 3H). m/z (ESI, +ve ion) 518.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].O=S(Cl)[Cl:20]>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][Cl:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Reactant: O=S(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1

Procedure:
114 g (0.49 mol) of 4-(trans-4'-propylcyclohexyl) benzyl alcohol was dissolved in 107 cm3 (1.05 mol) of SOCl2 and the solution was refluxed over a warm water bath for 5 hours. The excess SOCl2 was distilled off under reduced pressure and the residue was washed with 10% hydrochloric acid and water. The chloroform was distilled off under reduced pressure and the residue was distilled under reduced pressure (147° C./3.0 mmHg) to yield 114 g (0.45 mol) of 4-(trans-4'-propylcyclohexyl)-benzyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].O>C(OC)(C)(C)C>[C:17]([O:9][CH:4]1[CH2:5][CH:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]1)(=[O:21])/[CH:18]=[CH:19]/[CH3:20]
Reactant: C/C=C/C(=O)Cl
Reactant: CC1CC(O)CC(C)(C)C1
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: C/C=C/C(=O)OC1CC(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
71 g of 3,3,5-trimethylcyclohexanol having a cis content of 90% are placed in a 1-l reaction flask together with 60 g of pyridine in 300 ml of methyl tert-butyl ether and 63 g of crotonic acid chloride are added at 0 to 5° C. over 30 minutes. The reaction mixture is left to continue reacting for a further one hour at this temperature; it is then allowed to heat up to room temperature. After one hour it is heated for a further 30 min to 50° C. After cooling, it is fractionated with water, the organic phase is separated off and first washed with dilute hydrochloric acid and then stirred for a further 30 min with 5-percent sodium hydroxide solution. After washing until it is neutral, the solvent is drawn off and the residue distilled using a short column. 63 g of pure 3,3,5-trimethylcyclohexyl crotonate having a cis content of 90% are obtained at a boiling point of 121° C. under 20 mbar. MS: 210 (M*, 0,3), 195 (0,5), 141 (3), 124 (75), 109 (100), 95 (24), 87 (24), 82 (25), 69 (75), 55 (11), 41 (33). The cis-3,3,5-trimethylcyclohexyl esters of propionic acid, isobutyric acid and butyric acid can be prepared in an analogous manner.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:29]=[N:28][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]=3[CH:16]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: O=C1CCCCCC1=O
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccc(Cl)cc1C)OC
Solvent: O
Product: Cc1cc(Cl)ccc1-c1cc2c(nn1)CCCCC2

Procedure:
light brown solid. MS (EI): 272.2 (M+). Prepared from cycloheptane-1,2-dione, [2-(4-Chloro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9].[N:24]([O-])=O.[Na+].[CH3:28][NH:29][CH3:30]>C(O)(=O)C.C(O)(=O)CC.O.Cl>[CH3:28][N:29]([CH3:30])[N:24]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9]
Reactant: O=N[O-]
Reactant: CNC
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Agent: Cl
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N=NN(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-Amino-N-[(4-methoxy-6-methylpyrimidin-2-yl)-aminocarbonyl]benzenesulfonamide (3.0 g) in acetic acid (30 mL), propionic acid (20 mL), water (10 mL) and concentrated HCl (2.0 mL) was cooled to 0° C. To this mixture was added sodium nitrite (0.75 g) with stirring. The mixture was held at -10° to 0° C. for 45 minutes. The mixture was then added to an ice and water slurry containing dimethylamine (150 mL, 25% dimethylamine in water). The homogeneous solution was acidified with acetic acid and the heavy white precipitate filtered, washed with water and dried in vacuo, to afford 2.94 g of the title compound as a white solid, m.p. 158°-160° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[O:29])=[C:23]([C:39]#[N:40])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[C:39]([C:23]1[CH:22]=[C:21]([CH:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:29])#[N:40]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(C#N)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(NC(=O)Nc2ccc(C3CNCCO3)cc2C#N)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a stirred solution of trifluoroacetic acid (22 μl) in water (3 ml) was added a solution of (RS)-2-{3-cyano-4-[3-(3-cyano-phenyl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (13 mg) in acetonitrile (1.5 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-cyano-4-morpholin-2-yl-phenyl)-3-(3-cyano-phenyl)-urea (6 mg, 52%) as a light brown solid. MS (ISP): 348.1 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[SiH:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[SiH](CC)CC
Reactant: c1ccc(Cn2ccc3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2n1Cc1ccccc1
Yield: 31.1 %

Procedure:
The reaction was conducted according to the General Procedure by heating 1-benzylindole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 50 mg (31%) of the title compound as a colourless oily solid. 1H NMR (500 MHz, THF-d8) δ 7.56 (ddd, J=7.7, 1.3, 0.7 Hz, 1H), 7.25-7.07 (m, 4H), 7.02 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.98 (ddd, J=7.9, 6.9, 1.1 Hz, 1H), 6.92-6.86 (m, 2H), 6.80 (d, J=0.9 Hz, 1H), 5.52 (s, 2H), 1.06-0.88 (m, 9H), 0.85-0.69 (m, 6H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CO)cc1
Yield: 78.4 %

Procedure:
The compound of formula 2 (Z=trifluoromethylsulphonyloxy), methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)methyloxyacetate, was prepared as follows. Allyl bromide (4.4 g) was added to a stirred suspension of 4-hydroxybenzyl alcohol (4.34 g) and potassium carbonate (5.00 g) in butanone (40 ml). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled and then filtered. The filtrate was evaporated to give an oil which was purifed by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give 4-allyloxybenzyl alcohol (4.50 g) as a pale yellow oil; NMR(CDCl3): 1.81(1H,t), 4.48-4.65(4H,m), 5.22-5.48(2H,m), 6.05(1H,m), 6.90(2H,m) and 7.25(2H,m), m/z 164(H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)#[N:15]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2,4-difluorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=443, RT=0.71 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:25][C:24]3[C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:22][C:21]([C:32]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:33]=4[CH:34]=[N:35][NH:36]5)=[N:20][C:19]=3[CH:18]=2)[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>>[NH:36]1[C:37]2[C:33](=[C:32]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:24]4[S:25][C:17]([C:13]5[CH:12]=[C:11]([NH:10][C:9](=[O:41])[CH2:8][NH2:7])[CH:16]=[CH:15][CH:14]=5)=[CH:18][C:19]=4[N:20]=3)[CH:40]=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Yield: 20.4 %

Procedure:
Tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate (82 mg) was treated with 2 mL of trifluoroacetic acid/dichloromethane (1:1). Upon completion, the reaction mixture was evaporated. The product was purified by reverse phase HPLC to yield 13.9 mg of 137. MS (Q1) 486 (M)+.
Reaction SMILES: [I-:1].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:18])[CH3:3].[C:19]1([N:25](C2C=CC=CC=2)[CH:26]=N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CC(C)=O>[I-:1].[NH:25]([CH:26]=[CH:18][C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][C:8]=2[N+:4]=1[CH2:2][CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Reactant: N=CN(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC[n+]1c(C=CNc2ccccc2)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Intermediate E (1.0 g) and diphenylformamidine (2.2 g) were combined in a flask and heated over a hot air gun with manual stirring until a yellow-orange color formed. The reaction was then heated for 1 minute at full heat until it became totally liquid. On cooling to room temperature, the reaction mixture solidified. This solid was dissolved in 20 ml hot acetone, poured into 100 ml diethyl ether with stirring, and stirred for 1 hour. The solid was then filtered out and washed with diethyl ether to give 1.2 g of 2-(2-anilinovinyl)-3-ethyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate F).
Reaction SMILES: [C:1]([NH:9][C:10](=[S:23])[NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]([Br:22])[CH:13]=1)(=O)[C:2]1C=CC=CC=1.O1CCCC1.[OH-].[K+].Cl.CO>CO>[Br:22][C:14]1[CH:13]=[C:12]([NH:11][C:10]2[S:23][CH:2]=[CH:1][N:9]=2)[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=S)NC(=O)c2ccccc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(Nc2nccs2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2.37 g of methyl 6-(3-benzoylthioureido)-4-bromopyridine-2-carboxylate, 20 ml of tetrahydrofuran and 40 ml of methanol was added 673 mg of potassium hydroxide. The reaction mixture was stirred at room temperature for 1.5 hours, and acidified with a hydrochloric acid-methanol solution. The solvents were concentrated in vacuo. The resulting residue was dissolved in 60 ml of 1,4-dioxane and 3.53 ml of a 40% chloroacetaldehyde aqueous solution was added thereto. After the reaction mixture was heated under reflux for 1 hour, 40 ml of a hydrochloric acid-methanol solution and 60 ml of methanol were added thereto at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from methanol-diethyl ether to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][NH:22][CH2:23][C@H:12]23)[CH:17]=1.Cl[CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][CH2:19][N:14]3[C@@H:13]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[O:29])[CH2:23][C@H:12]23)[CH:17]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CC3)c(Cl)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3)c1ccc(F)cc1
Yield: 37.2 %

Procedure:
The title compound (36 mg, 37%) was prepared by the method of Example 189 from (±)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (65.8 mg, 0.19 mmol), 4-chloro-4′-fluorobutyrophenone (50.0 mg, 0.25 mmol), KI (31.5 mg, 0.19 mmol), and K2CO3 (50.0 mg, 0.57 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.90-7.95 (m, 2 H), 7.37 (s, 1H), 7.16 (s, 2H), 7.03 (t, 2H, J=8.8 Hz), 6.91 (s, 1H), 6.85 (s, 1H), 3.49 (bt, 1H, J=8.0 Hz), 3.25-3.45 (m, 2H), 3.02-3.22 (m, 2H), 2.90-3.02 (m, 3H), 2.50-2.88 (m, 2H), 2.10-2.45 (m, 4H), 1.70-2.00 (m, 4H) ppm. MS (CI, NH3): 509 (base, M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1C2C(OC(=O)N(C)[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)=[S:23])C3C(=CC=CC=3)C=2C=CC=1.[Br:34][CH2:35][C:36](=O)CC>N1CCCCC1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:2]2[S:1][CH:5]=[C:4]([CH2:35][CH3:36])[N:3]=2)=[CH:26][CH:27]=1.[Br:34][C:22]1[S:23][CH:30]=[CH:25][N:24]=1
Reactant: c1cscn1
Reactant: CN(C(=O)OC1c2ccccc2-c2ccccc21)C(=S)Nc1ccc(Br)cc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Brc1nccs1
Product: CCc1csc(Nc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Procedure for thiazole synthesis: 9H-9-fluorenyl-methyl-N-[(4-bromoanilino)carbothioyl]carbamate (0.25 g, 0.55 mmol) was dissolved in piperidine/N,N-dimethylformamide (1:6, 3.5 mL) and the mixture stirred at ambient temperature for 2 h. The solvent was removed under reduced pressure and the residue dissolved in a mixture of acetic acid (1 mL), ethanol (2 mL), and dioxane (2 mL). 1-Bromo-2-butanone (90%, 0.11 mL, 1.10 mmol) was added and the mixture was stirred for 14 h at ambient temperature. The reaction mixture was diluted with half saturated aqueous sodium carbonate (15 mL) and extracted with methanol/dichloromethane (1:19, 3×20 mL). The combined organic layers were dried (magnesium sulfate), filtered, concentrated and purified by flash column chromatography on silica gel using ethyl acetate/heptane (1:4) to afford the bromothiazole N-(4-bromophenyl)-N-(4-ethyl-1,3-thiazol-2-yl)amine (0.15 g, 0.53 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 13.15 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:23]#N.[K+]>C(O)C#C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]#[CH:23])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: C#CCO
Agent: [K+]
Product: C#CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 40 h

Procedure:
A mixture of 20.0 g (62.5 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.0 g (15.4 mmol) of potassium cyanide and 100 ml of propargyl alcohol is stirred at 130° for 40 hours, about 50 ml of solvent being distilled off in vacuo after 16 hours and 50 ml of propargyl alcohol being added to the mixture. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in chloroform, the chloroform solution is washed once with water and once with saturated sodium chloride solution and dried over magnesium sulphate. The magnesium sulphate is removed by filtration under suction and the chloroform solution is filtered through silica gel, elution being subsequently carried out with ethyl acetate. After evaporation of the eluate, the residue is recrystallized twice from chloroform/toluene and once from ethanol, there being obtained 2-propynyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate of melting point 198°-200°.