Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([CH:17]=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1.O1[CH2:29][CH2:28]OCC1>O.[Cu]I>[N:19]1[N:20]([C:29]2[C:28]([C:17]([N:15]3[CH2:14][CH:12]4[CH:11]([CH2:10][N:9]([C:4]5[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:13]4)[CH2:16]3)=[O:18])=[CH:6][CH:7]=[CH:2][N:3]=2)[N:21]=[CH:22][CH:23]=1
Reactant: c1c[nH]nn1
Reactant: Cc1cc(C)nc(N2CC3CN(C=O)CC3C2)n1
Reactant: C1COCCO1
Agent: [Cu]I
Solvent: O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-n4nccn4)CC3C2)n1
Yield: 6 %

Procedure:
To a solution of 2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (Example 234) (150 mg, 0.37 mmol), 1H-1,2,3 triazole (43 μL, 0.75 mmol), CsCO3 (247 mg, 0.75 mmol), in H2O (2 μL) and 1,4 dioxane (2 mL) was added (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexyldiamine (12 μL, 0.75 mmol) and CuI (3.5 mg, 0.86 mmol). The reaction mixture was irradiated in a microwave reactor at 160° C. for 2 h. The resulting solution was filtered through Celite®, washed with DCM, and concentrated. Purification (FCC)(MeOH(NH3)/DCM) gave the title compound (8 mg, 6%). MS (ESI): mass calculated for C20H22N8O, 390.19; m/z found 391.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.65 (dd, J=4.8, 1.8, 1H), 7.83 (dt, J=13.3, 6.6, 2H), 7.43 (dt, J=7.6, 4.5, 1H), 6.38-6.23 (m, 2H), 4.02-3.28 (m, 6H), 3.10-3.06 (m, 4H), 2.42-2.22 (m, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)cn1
Yield: 11 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (72.9 mg, 0.3 mmol) was converted, using 3-trifluoromethylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 11%) which was obtained as an off-white solid. MS: m/e=388.6 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=N[N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CC=C(B(O)O)[CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[N:14][CH:16]=[CH:18][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cccnc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using pyridin-3-ylboronic acid. ESI-MS (m/z): 214 [M+1]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)(C)(C)C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][C@@H:20]([NH2:19])[CH2:21]1
Reactant: Fc1ccc2nccc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: N[C@@H]1CCN(c2ccnc3ccc(F)cc23)C1

Procedure:
Starting from 4-bromo-6-fluoroquinoline (commercial) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (212 mg, 43% over two steps).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[C:43]1([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(OCC)(=O)C.O1CCCC1>[Cl-:21].[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH2:20][P+:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC=O)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Product: [Cl-]
Yield: 49.9 %

Procedure:
To a solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (25.0 g) in ethyl acetate (300 ml) was added a solution of triphenylphosphine (21.0 g) in tetrahydrofuran (170 ml), and the mixture was heated under reflux for 10 hours. The precipitated substance was collected by filtration to give [7-{2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido}-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenylphosphonium chloride (syn isomer) (17.7 g). The remained filtrate was heated under reflux for 10 hours. Similarly, the precipitated substance was collected by filtration to recover the same product (9.75 g). Further, this operation was repeated once to recover the same product (3.3 g). Total yield: 30.75 g.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@:7]2([CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]1=[O:21].CN(C)C(=O)CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O.[CH2:47]([O:54][CH2:55][C@@H:56]([NH:60][C:61](=[O:73])[C:62]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])([CH3:64])[CH3:63])[C:57](O)=[O:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[CH2:47]([O:54][CH2:55][C@@H:56]([NH:60][C:61](=[O:73])[C:62]([NH:65][C:66](=[O:67])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:64])[CH3:63])[C:57]([N:17]1[CH2:18][CH2:19][CH2:20][C:7]2([C:6](=[O:21])[N:5]([CH2:4][C:3]([N:2]([CH3:23])[CH3:1])=[O:22])[CH2:9][CH:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16]1)=[O:58])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CN(C)C(=O)CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)C(=O)CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A racemic mixture of (4R,5S)—N,N-dimethyl-2-(1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-2-yl)acetamide and (4S,5R)—N,N-Dimethyl-2-(1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-2-yl)acetamide (Intermediate 1D) (193 mg; 0.612 mmol) was solubilised in acetonitrile (3 ml). (R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)-propionic acid (Intermediate 3A) (233 mg; 0.612 mmol) was treated with DIPEA (0.427 ml; 2.448 mmol) and ®T3P (50% in EtOAc), (0.714 ml; 1.224 mmol). The mixture was stirred at RT for 2 hours and concentrated in vacuo. The crude residue was solubilised in ethyl acetate and washed with water (3×50 ml). The organics were washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: [P:1]([O-:28])([O:24][CH2:25][CH2:26]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[P:1]([O-:28])([O:24][CH2:25][CH2:26][N+:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Product: CCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccc1

Procedure:
2-[2-(Tetradecyloxy)ethoxy]ethyl 2-bromoethyl phosphate obtained in Example 26 is reacted with pyridine and a conventional purification procedure of the reaction mixture gives the title compound as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH3:9][C:5]1[N:4]=[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:42]([CH2:41][CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:1][C:2]2=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CCCc4ccccc4)nc4c(C)cc(C)nc43)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 29 %

Procedure:
A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 4 of Example 162, 86 mg, 0.19 mmol), 4-phenylbutyric acid (37 mg, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was stirred at room temperature for 5 days. The mixture was concentrated to give an orange syrup. This material was dissolved in toluene (8 ml), added p-toluenesulfonic acid mono-hydrate (3 mg, 0.02 mol), then stirred under reflux temperature for 5 h. The mixture was diluted with dichloromethane and washed with diluted hydrochloric acid. The organic layer was concentrated. Purification by TLC developing with hexane/ethyl acetate (1:3) gave 32 mg (29%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][OH:25])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[CH2:23][CH2:24][O:25][S:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=3)(=[O:48])=[O:49])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)CCOS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-3-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-butan-1-ol (0.245 g, 0.548 mmol) in dichloromethane (10 mL) is added triethylamine (0.15 mL, 1.09 mmol). After 10 minutes, m-nitrobenzene sulfonyl chloride (0.243 g, 1.09 mmol) is added. The reaction is stirred at room temperature for 4 hours and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.28 (d, 6H), 1.62 (s, 2H), 1.85-1.95 (m, 2H), 2.17 (s, 3H), 2.91-3.039 (m, 2H), 3.85-3.95 (m, 1H), 4.04-4.12 (m, 2H), 4.74 (s, 2H), 6.45 (d, 1H), 6.51 (dd, 1H), 6.86 (d, 1H), 7.26 (t, 1H), 7.38 (d, 2H), 7.65 (t, 3H), 8.1 (d, 1H), 8.39 (d, 1H), 8.63 (s, 1H);
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]#[N:16])=[CH:7][N:8]2[CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([N:1]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:10]=3)[C:6]([C:15]#[N:16])=[CH:7]2)[CH2:14][CH2:13][CH2:12]1
Reactant: BrCCOCCBr
Reactant: N#Cc1cn(C2CCC2)c2cc(N)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cn(C2CCC2)c2cc(N3CCOCC3)ccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 6-amino-1-cyclobutyl-3-cyanoindole (4.60 g, 21.8 mmol), bromoethylether (6.07 g, 26.16 mmol), DIEA (10.79 mL, 65.4 mmol) in DMF (100 mL) was stirred at 90° C. overnight and then poured into ice-water (1.0 L). The precipitate was filtered, washed with water, and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (5.24 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.C1C=CC=CC=1.N12CCCN=C1CCCCC2.[C:33]([OH:36])(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[C:33]([O:36][CH2:14][C:5]1[C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([Br:1])[CH:3]=2)[O:8][C:7](=[O:13])[CH:6]=1)(=[O:35])[CH3:34]
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCc1cc(=O)oc2cc(O)c(Br)cc12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of 67.1 mg (0.232 mmol) of compound 11, dry benzene (2 mL), 175 mL (0.927 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 mL (0.70 mmol) of acetic acid was refluxed for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (10 mL), quenched with 1N HCl (1 mL) and separated. The organic layer was dried over MgSO4 and evaporated to yield the crude product. Purification by column chromatography (10 g of SiO2, 4.7% methanol-chloroform) gave 43.1 mg (0.138 mmol, 59.4% yield) of compound 5 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.56 (1H, s), 6.80 (1H, s), 6.21 (1H, s), 5.14 (2H, s), 2.11 (3H, s); MS (ES, negative) 311.0 and 313.1; UV (KMOPS, pH 7.2) λmax (ε) 370 nm (15,000 M−1cm−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[S:3]1)[S:11][C:10]([CH3:15])([CH3:14])[S:9]3.[Li]CCCC.[CH3:22][S:23]SC>C(OCC)C>[CH3:22][S:23][C:13]1[C:4]2[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[S:11][C:12]=12
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1c2c(cc3c1SC(C)(C)S3)SC(C)(C)S2

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole is lithiated with n-BuLi in diethyl ether and then reacted with dimethyl disulfide to give 4-methylthio-2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole. This compound can then be reacted with n-butyl glyoxalate (0.5 eq.) in a solvent consisting of a mixture of concentrated sulfuric acid and glacial acetic acid (1:10) (analogously to: G. Werber, Ann. Chim. 49, 1898 (1959)). After work-up, including neutralization and extraction the product is purified by preparative HPLC. The n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate formed can be hydrolyzed with a 10% solution of sodium hydroxide and transferred into other esters, amides, thioesters and anhydrides etc. by standard procedures. If n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate is treated with n-BuLi (3 eq.) in tetrahydrofurane at ambient temperature and exposed to oxygen, the initially formed enolate anion is oxidized to the stable title radical (analogously to P. O'Neill and A. F. Hegarty, J. Org. Chem. 52, 2113 (1987)).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Br>>[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)/[CH:18]=[C:2]1\[CH2:3][CH2:4][C:5]2[NH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:9]\1=2
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Br[Mg]Cc1cccc(Br)c1
Product: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(Br)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Br)c1

Procedure:
The title compound was synthesized in two steps. Methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1.50 g, 8.37 mmol) was reacted with 3-bromobenzylmagnesium bromide (84 mL, 21 mmol) according to General Procedure 3 to give (E)-methyl 4-(3-bromobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane to afford the title compound: 1.034 g. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.03-2.11 (m, 1H), 2.47-2.56 (m, 1H), 2.59-2.73 (m, 2H), 2.78 (d, 7.47 Hz, 2H), 3.24-3.32 (m, 1H), 3.72 (s, 3H), 6.32 (d, 1.76 Hz, 1H), 7.20-7.28 (m, 3H), 7.37-7.40 (m, 1H), 7.43 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].[CH2:43](I)[CH3:44].O>CN(C)C=O.C(OCC)(=O)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:43][CH3:44])[C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (980 mg) is dissolved in N,N-dimethylformamide (10 ml), and thereto is added sodium hydride (60%) (91 mg) under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (182 μl) and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (425 mg). MS (m/z): 673/675 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]1[C:16]1C=CC=C[CH:17]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:45]#[C:46][C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]#[C:45][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH:3]([CH2:16][CH3:17])[C:4]2=3)=[CH:48][CH:49]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CCC1c2c(c3cc(C)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (276 mg, μmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (90 mg). 1H NMR (CDCl3) FREE BASE7.40-7.20 (m, 9H), 7.16-7.12 (d, 1H), 7.08-7.04 (d, 2H), 4.73 (s, 1H), 3.22-3.16 (m, 1H), 3.0-2.80 (m, 3H), 2.50 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 63 %

Procedure:
Upon boiling a solution of 15.1 g 3-nitrobenzaldehyde and 26.0 g amidinoacetic acid ethyl ester in 250 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 175° - 176° C. (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[C:4]([F:14])[C:3]=1[Br:20]
Reactant: BrBr
Reactant: CCOc1cc(Br)cc(F)c1OCC
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(Br)c(Br)c(F)c1OCC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To a solution of 5-bromo-1,2-diethoxy-3-fluorobenzene (40.0 g, 0.15 mol) in acetic acid (200 mL), sodium acetate (16.2 g, 0.20 mol) and bromine (31.6 g, 0.20 mol) were added sequentially at room temperature, and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium thiosulfate (400 mL) and water (400 mL) were added sequentially. The mixture was extracted once with heptane (800 mL) and three times with heptane (400 mL). The organic layer was washed sequentially with water (400 mL), once with a 2 N aqueous solution of sodium hydroxide (200 mL), once with a 2 N aqueous solution of sodium hydroxide (100 mL), and water (400 mL), then dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer under reduced pressure and the residue was filtered. The filtrate was then purified by silica gel column chromatography (hexane, ethyl acetate) to give 52.0 g of the title compound (yield:quant.).
Reaction SMILES: N[C:2](N)=[O:3].[CH:5]1([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1>>[CH:5]1([N:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH3:18])[CH2:16][CH2:17]2)[C:2]([NH:19][C:20]2[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=2)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1ncc(C=O)s1
Reactant: NC(N)=O
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1

Procedure:
Prepared in 40% (140 mg) yield as described for 1,1-dicyclohexyl-3-5-formyl-thiazol-2-yl)-urea using cyclohexyl-(trans-4-methyl-cyclohexyl)-amine (195 mg, 1.0 mmol) and 2-amino-5-formylthiazole (128 mg, 1.0 mmol).