Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1>C(Cl)(Cl)Cl>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3
Temperature: 180 °C
Yield: 5655.1 %

Procedure:
A mixture of 2.9 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline 3-carboxylate and 0.03 g of p-toluenesulfonic acid was melted and heated at 180°C (bath temperature) for 2 hours and cooled. The product was dissolved in chloroform, washed with a dilute aqueous sodium carbonate solution and then with water. The chloroform layer was separated and evaporated to dryness. There was obtained 2.85 g of pure ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate, m.p. 175°-177°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:10])=[N:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(Cl)ncc1N
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(I)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
5-Amino-2-chloro-4-methylpyridine (1.35 g) was dissolved in DMF (20 mL), N-iodosuccinimide (2.59 g) was added and the reaction mixture was stirred at room temperature for 12 hours. Ethyl acetate was added and the organic layer was washed 3× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.30) to afford 1.38 g of the title compound of the formula
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.[C:25]([C:29]1[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]2[O:33][P:34](Cl)[O:35][C:36]3[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:38][C:37]=3[C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CCCCCC.O1CCCC1>[C:46]([C:39]1[CH:40]=[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]2[O:35][P:34]([C-:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[O:33][C:32]3[C:51]([C:53]([CH3:55])([CH3:54])[CH3:56])=[CH:52][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][C:31]=3[C:37]=2[CH:38]=1)([CH3:49])([CH3:48])[CH3:47].[C-:6]1([P:34]2[O:35][C:36]3[C:41]([C:42]([CH3:43])([CH3:44])[CH3:45])=[CH:40][C:39]([C:46]([CH3:48])([CH3:49])[CH3:47])=[CH:38][C:37]=3[C:31]3[CH:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]=3[O:33]2)[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a solution of 9.5 g (50 mmol) of ferrocene in 250 mL of hexane is added dropwise 67 mL of a 1.6M solution of n-butyl lithium at ambient temperature. The reaction mixture is stirred for 20 minutes and then to the resultant red suspension is added 12.0 g (103 mmol) of N,N,N',N'-tetramethylethylenediamine. A slight exotherm of 10° C. is observed. The reaction mixture is then heated at reflux for two hours during which time an orange suspension forms. The reaction mixture is cooled to room temperature and 100 mL of tetrahydrofuran is then added. The reaction mixture is cooled to -40° C. Then to the cooled reaction mixture is added dropwise a solution of 51.8 g (109 mmol) of 2,4,8,10-tetrakis(tert-butyl)-6-chloro-dibenzo[d,f][1,3,2]dioxaphosphepin in 100 mL of tetrahydrofuran. The reaction mixture is allowed to warm to ambient temperature after the addition is complete. The reaction mixture is then heated at reflux for six hours. After cooling, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue formed is triturate with 150 mL of hexane. The resultant solid is recrystallized from acetonitrile/tetrahydrofuran mixture to give 25 g (47% yield) of a light brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[O:8][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=4)[O:8][CH:7]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: COc1cc2occ(CCCCBr)c(=O)c2cc1OC
Product: COc1cc2occ(CCCCN3CCN(c4cccc(O)c4)CC3)c(=O)c2cc1OC
Yield: 17 %

Procedure:
Using the same starting material, 3-(4-bromobutyl)-6,7-dimethoxychromen-4-one obtained in Step 3 of Example 1, but with 3-hydroxyphenylpiperazine, and using a microwave reaction vessel (15 min, 160° C., 150 w), 3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6,7-dimethoxychromen-4-one is obtained in a similar manner to Example 1 in a yield of 17%. M.p. ° C.=177-180; analytical HPLC Sym C8, 4.6×250 mm, 5μ, eluant: CH3CN—H2O, KH2PO4 25-75-6.8 g/l, pH4, r.t.=9.99 min; MS ESI, m/z=439 (MH+); 1H NMR (CDCl3): 7.72 (s, 1H), 7.55 (s, 1H), 7.09 (t, 1H, J=8 Hz), 6.83 (s, 1H), 6.49 (d, 1H, J=8.28 Hz), 6.39 (s, 1H), 6.31 (d, 1H, J=7.84 Hz), 3.97 (s, 6H, OCH3), 3.18 (m, 4H), 2.58 (m, 4H), 2.49 (m, 2H), 2.43 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: C(C1C=CC([CH:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)=[CH:13][CH2:12]2)=CC=1)CCC.[CH2:26]([C:30]1[CH:35]=[CH:34][C:33](C2CCC(=O)CC2)=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29].BrC1C=C(F)C(F)=C(F)C=1>>[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([C:13]2[C:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=3)=[CH:15][CH:16]=[CH:11][CH:12]=2)=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1ccc(C2CC=C(c3cc(F)c(F)c(F)c3)CC2)cc1
Reactant: CCCCc1ccc(C2CCC(=O)CC2)cc1
Agent: Fc1cc(Br)cc(F)c1F
Product: CCCCc1ccc(-c2ccccc2-c2cc(F)c(F)c(F)c2)cc1

Procedure:
Using 1-[4-(4-butylphenyl)cyclohexen-1-yl]-3,4,5-trifluorobenzene obtained by reacting 4-(4-butylphenyl)-cyclohexanone with 1-bromo-3,4,5-trifluorobenzene, as a starting raw material, 4"-butyl-3,4,5-trifluoroterphenyl was obtained in the same manner as in Example 3.
Reaction SMILES: Cl.F[C:3]1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[N:70][C:71]([N:74]5[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]5)=[CH:72][CH:73]=4)[CH:66]=3)[N:61]([S:80]([C:83]3[CH:89]=[CH:88][C:86]([CH3:87])=[CH:85][CH:84]=3)(=[O:82])=[O:81])[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:3][N:77]1[CH2:78][CH2:79][N:74]([C:71]2[N:70]=[CH:69][C:68]([C:65]3[CH:66]=[C:67]4[C:59]([C:57]5[CH:56]=[N:55][N:54]([CH2:46][CH2:47][C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)[CH:58]=5)=[CH:60][N:61]([S:80]([C:83]5[CH:84]=[CH:85][C:86]([CH3:87])=[CH:88][CH:89]=5)(=[O:81])=[O:82])[C:62]4=[N:63][CH:64]=3)=[CH:73][CH:72]=2)[CH2:75][CH2:76]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Yield: 99 %

Procedure:
Using similar reaction conditions as described in step-iii of example-133, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 2 of example 140) (50 mg, 0.082 mmol) was methylated using paraformaldehyde (8 mg, 0.24 mmol) and Na(OAc)3BH (35 mg, 0.164 mmol) in dichloroethane (10 mL) to afford 50 mg (99% yield) of the titled compound. MS: m/z=618.2 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH2:12])=O.N1C=CC=CC=1.O=P(Cl)(Cl)Cl>CCOC(C)=O.CCCCCC>[C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)#[N:12]
Reactant: NC(=O)c1nc2ccccc2s1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Benzothiazole-2-carboxamide 8 (0.61 mmol, 0.1 g) was dissolved in anhydrous pyridine (0.080 mol, 6.5 ml) and stirred under N2 at 0° C. The temperature of the reaction was dropped to 0° C. during dropwise addition of POCl3 (0.015 mol, 1.4 ml). The solution immediately changed from clear to a pale pink coloring with addition of POCl3. After 20 min, the acetone/ice bath was removed and the reaction was stirred at RT for 2 h further. The tan/brown-colored reaction was then transferred to a larger reaction flask containing 10 ml EtOAc at 0° C. The reaction was quenched by the dropwise addition of water. The organic product 10 was washed with water, extracted with EtOAc, and concentrated in vacuo to yield a light yellow/orange product. TLC analysis (3 Hexane: 2 EtOAc) and Agilent HPLC displayed 100% conversion to the desired product (single peak at 10.5 min). The compound was used in the subsequent step without purification (95% yield). ESI-MS: m/z calcd for C8H4N2S 161.01 (M+H)+, 160.86 found (100%). (see LC/MS spectra of FIG. 19A and NMR spectra of FIG. 19B).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21](Br)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[OH:45].O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:41]3[CH:42]=[CH:43][C:44]([OH:45])=[C:39]([F:38])[CH:40]=3)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(CC)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(O)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1(CC)CN(Cc2cc(-c3ccc(O)c(F)c3)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 33.5 %

Procedure:
To a solution of 150 mg 4-[6-Bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2-diethyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 48 mg 3-fluoro-4-hydroxy-phenylboronic acid in 8 ml of DEM and 0.45 ml of water were added 40 mg of potassium carbonate. To the degassed reaction mixture 4 mg of bis(tri-tert-butyl-phosphin)palladium(0) were added. The reaction was heated to 120° C. in a microwave reactor for 2 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried and concentrated in vacuo. The resulting residue was purified by HPLC. 53 mg (34%) of the title compound were obtained.
Reaction SMILES: [B-].[Na+].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[NH2:22])[CH:19]=3)[N:14]3[N:36]=[N:37][N:38]=[C:13]3[N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(Cl)Cl>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[NH2:22])[CH:19]=3)[N:14]3[N:36]=[N:37][N:38]=[C:13]3[NH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(N)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: [B-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1ccc(C(N)(c2ccc3c(c2)C(c2cccc(Cl)c2)Nc2nnnn2-3)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Sodium hydroborate (0.0005 mol) was added portionwise at room temperature to a mixture of intermediate 27 (0.0005 mol) in methanol (2.5 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over kromasil® (5 μm) (eluent: DCM/MeOH/Et3N 97/3/0.3). The pure fractions were collected and the solvent was evaporated. The residue (0.1 g, 40%) was taken up in diethyl ether and dried in a vacuo, yielding 0.07 g (28%) of 5-(3-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine (intermediate 28), mp. 140° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].O[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(OC[C@H](F)CCCCCC)=CN=1>C1COCC1>[F:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][O:16][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCCCCC[C@@H](F)CO
Reactant: Oc1ncccn1
Agent: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(F)COc1ncccn1
Yield: 140.5 %

Procedure:
(R)-(31)-2-[2',3'-difluoro-4'-(trans-4"-pentylcyclohexylethyl)phenyl]-5-(2-fluorooctyloxy)pyrimidine 49.-Quantities: DEAD (448 mg, 2.58 mmol) in THF (3 ml), (R)-(+)-2-fluorooctanol (379 mg, 2.58 mmol), hydroxypyrimidine 48 (1.0 g, 2.58 mmol), triphenylphosphine (676 mg, 2.58 mmol). The experimental procedure was as described for compound 34. The crude product was purified by flash chromatography (5 to 7% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 49 (820 mg, 61%) (from EtOH), transitions/° C. K 102.2 N* 128.3 I; [α]D26 -2.4° (c 2.0 in CHCl3); νmax /cm-1 (KBr) 2920, 2845, 1540, 1460, 1435s, 1285 1080, and 900; δ 0.80-1.03 (10 H, m), 1.06-1.45 (16H, m), 1.55 (4H, m), 1.82 (6 H, m), 2.71 (2 H, t J 8, ArCH2), 4.22 (2 H, dd, 3JHF 22 and J 4, OCH2), 4.86 (1 H, d of sext, 2JHF 48 and J 4, CHF), 7.01 (1 H, ddd, J 7.5, 7 and 1.5, 5'-H), 7.67 (1 H, ddd, J 7.5, 7 and 1.5, 5'-H), and 8.53 (2 H, s, 4- and 6-H); m/z 518 (M+), 489, 475, 461, 447, 365 and 353.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.[Cl-].[Cl-].[Zn+2]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 43 h
Yield: 58 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 15 min. The solution was cooled to 0° C., then treated with a solution of ZnCl2 (0.545 g; 4.00 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then THF (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (2 ml). The reaction mixture was then heated to 65° C. and stirred for 43 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.16 mmol (58% yield) of diphenylacetylene and 0.66 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=1
Reactant: c1c[nH]nn1
Reactant: Cc1cc(Cl)cc(N)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-n2ccnn2)cc(N)n1
Temperature: 150 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (100 mg, 0.701 mmol) and 1,2,3-triazole (0.133 mL, 2.30 mmol) in a pressure tube was added DIPEA (0.185 mL, 1.06 mmol). The reaction mixture was sealed and heated at 150° C. for 1.5 hours. The reaction mixture was cooled, diluted with DCM (20 mL), and washed with water (10 mL). The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried in 5% methanol/ethyl acetate (5 mL) and sonicated. The mixture was filtered, and the collected solids were dried under reduced pressure to afford 6-methyl-4-(1H-1,2,3-triazol-1-yl)pyridin-2-amine. MS ESI calc'd. for C8H10N5 [M+H]+ 176. found 176. 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.95 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 6.28 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1CCNC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-pyrrolidinol (5.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.9 mg). HRMS calcd for C15H16N2O3: 272.1161, found 272.1157.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(O)c2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using tert-butyl N-(3-bromobenzyl)carbamate instead of tert-butyl N-(4-bromobenzyl)carbamate and 3-hydroxyphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH2:16](C1C=CC(C=O)=CC=1)[CH3:17].FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: CCc1ccc(C=O)cc1
Agent: O=Cc1ccc(F)cc1
Product: CCc1ccc(C(Cl)C(=O)C(=O)OC)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 4-ethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Cl>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(Cl)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,4-dichlorobenzyl chloride
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)[C:15]1[CH2:14][CH2:13][CH:12]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH2:11][C:10]2=1.[OH-].[Na+]>C(O)C.Cl>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:16]1[C:15]2[CH2:14][CH2:13][CH:12]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH2:11][C:10]=2[C:9]2[C:17]1=[CH:18][CH:19]=[C:7]([Cl:6])[CH:8]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2[N+](=O)[O-])C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2N)C1

Procedure:
Dissolve tin(II) chloride dihydrate (2.15 g, 9.5 mmol) in absolute ethanol (10 mL) and add it to N-[6-chloro-9-(2-nitro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 104) (810 mg, 1.9 mmol) in concentrated hydrochloric acid (10 mL). Heat the reaction at 60° C. for 1.5 h. Allow to cool and add 5N NaOH (27 mL) until pH=11-12. Extract the suspended solids into ethyl acetate (4×). Combine the organic portions and wash with water, brine, dry (MgSO4), and concentrate in vacuo to obtain a solid. Pass over a silica pad eluting with 25% ethyl acetate/dichloromethane to obtain 640 mg (85%). MS (ES): m/z 396, 398 (M+1), 394 (M−1); 1H NMR(DMSO-d6): δ 7.86 (d, 1H, J=7.5 Hz), 7.49 (d, 1H, J=1.8 Hz), 7.24 (d, 1H, J=8.8 Hz), 7.04 (dd, 1H, J=8.6, 2.0 Hz), 6.93 (dt, 1H, J=7.5, 1.3 Hz), 6.71 (dd, 1H, J=8.1, 1.1 Hz), 6.37 (dt, 1H, J=7.5, 1.3 Hz), 5.89 (d, 1H, J=7.0 Hz), 5.14 (m, 4H), 4.03 (m, 1H), 2.98 (dd, 1H, J=15.2, 5.1 Hz), 2.75-2.60 (m, 2H), 2.55 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H), 1.81 (m, 1H), 1.03 (d, 3H, J=4.0 Hz), 1.02 (d, 3H, J=4.4 Hz).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>[Pd]>[F:20][C:2]([F:19])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 4-Trifluoromethyl-thiazol-2-ylamine instead of 2-Chloro-4-aminopyridine to yield [6-Methyl-2-(4-trifluoromethyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white solid. MS (ISP): m/e=403.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=303.0 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, MS (ISP): m/e=380.0 (M+H+).