Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CO>[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:19][CH:20]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6]
Reactant: C1COCCN1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Acetic acid (0.37 ml, 6.44 mmol) was added dropwise to a mixture of 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (730 mg, 1.29 mmol), morpholine (0.225 ml, 2.58 mmol), 3A powdered molecular sieves (730 mg) and MeOH (21 ml). This was left to stir overnight under N2. The mixture was then evaporated in vacuo and the resultant crude partitioned between CH2Cl2 (3×40 ml) and sat. NaHCO3 solution (40 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give crude 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (810 mg) as a yellow solid, LC/MS: RT=2.365 min. 638.4 (MH+).
Reaction SMILES: NC1NC=NC=1C(N)=O.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]
Reactant: CN=C=O
Reactant: [N-]=[N+]=C1NCN=C1C(N)=O
Agent: NC(=O)c1nc[nH]c1N
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=O)ncn2c1=O

Procedure:
Med. Chem. 1984, 27, 196-201 describes a process wherein 5-amino-1H-imidazole-4-carboxamide is converted into 5-diazo-1H-imidazole-4-carboxamide, which is then cyclised with methylisocyanate in dichloromethane to provide a high yield of temozolomide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:4][CH:3]=1.C[CH2:26][O-:27].[Na+].O>CO.C1(C)C=CC=CC=1>[ClH:1].[CH3:26][O:27][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: Clc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1
Product: Cl
Yield: 24 %

Procedure:
According to the literature procedure (Trecourt, F.; Mallet, M.; Mongin, O.; Queguiner, G. J. Org. Chem. 1994, 59, 6173.), a solution of (E)-1-(6-chloropyridin-2-yl)-2-styryl-1H-benzimidazole (145 mg, 0.44 mmol), 28% NaOEt in MeOH (3 ml) and toluene (5 ml) was maintained at room temperature for 2 h then heated under reflux condition for 1 h. To this solution, water (1 ml) was added and it was concentrated by evaporator. To this residue, water (5 ml) was added and the whole was extracted with CH2Cl2 (2×15 ml). Combined organic layer was dried (magnesium sulfate) and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 20 g; n-hexane/ethyl acetate (5/1)) to afford the desired compound (35 mg, 24%). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][C:63](O)=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:63](=[O:64])[CH2:62][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][N:56]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)Nc1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(-c2ccc3nc(NC(=O)Cc4ccccn4)sc3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (121.8 mg, 0.382 mmol) and HATU (215.9 mg, 0.568 mmol) were suspended in DCM (2.9 ml) and diisopropylethylamine (0.21 ml, 1.2 mmol) and 2-pyridylacetic acid hydrochloride (94.3 mg, 0.543 mmol) were added. The reaction was stirred under nitrogen at room temperature overnight, concentrated and purified on a silica gel column (20:1 DCM/MeOH). Fractions with product were collected, concentrated, and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes). Fractions with product were collected, concentrated, and dried under high vacuum in a water bath (˜50° C.), then at room temperature overnight to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)-2-(pyridin-2-yl)acetamide (57.5 mg, 34% yield). MS (ESI pos. ion) m/z: 438. Calculated exact mass for C22H20ClN5OS 437.
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)C.[CH:35]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH:48]([CH3:50])[CH3:49])[CH:46]=1)[CH:42]=O)([CH3:37])[CH3:36].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:35]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH:48]([CH3:50])[CH3:49])[CH:46]=1)[CH2:42][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:37])[CH3:36]
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OC(C)C)c1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 479.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30](Cl)=[O:31])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=[CH:21][CH:22]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccnc2ccccc12
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccnc2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-4-carbonyl chloride were combined to provide N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-quinolinecarboxamide as a white crystalline solid, m.p. 214.5-215.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J=4.3 Hz, 1H), 8.76 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.10-8.01 (m, 3H), 7.78 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.56 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.44 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.34 (d, J=4.3 Hz, 1H), 7.24 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 6.60 (broad s, 2H), 4.68 (t, J=6.9 Hz, 2H), 3.38 (q, J=7.0 Hz, 2H), 2.00 (m, 2H), 1.63 (m, 2H); MS (EI) m/e 410.1860 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].[Cl-]>O.ClCCl>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)cnn1CC
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A 30-ml eggplant type flask was charged with 0.25 g (0.69 mmol) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 5 ml of dichloromethane, 5 ml of water and 0.09 g (0.69 mmol, 1 equivalent) of potassium carbonate, and 0.11 g (0.76 mmol, 1.1 equivalents) of n-propanesulfonyl chloride was dropwise added with stirring at room temperature. 5 mg of benzyltriethylaminonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.35 g of a crude product, which was recrystalized from ethanol to give 0.31 g (yield 95%) of 4,5,8-trimethyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:7]1[N:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:9][N:8]=1.Cl.O1CCOCC1>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:7]1[N:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (180 mg) is added 4N-hydrochloric acid/dioxane solution (2 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. 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 (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-dichlorobenzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (136 mg). MS (m/z): 664/662 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:13]2[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:14]=2[N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1.N1C=CC=C[CH:30]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[C:13]3[S:24][C:23]([C:25]([O:27][CH2:28][CH3:30])=[O:26])=[CH:22][C:14]=3[N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)n1nc(N)c2sc(C(=O)OC)cc21
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)c(NC(=O)c1ccc(F)cc1)nn2C(=O)OCC
Temperature: 5 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A solution of 4-fluorobenzoyl chloride (0.106 mol, 12.7 mL) in 50 ml of anhydrous dichlorometane was added dropwise to an ice-cold suspension of 1-ethyl 5-methyl 3-amino-thieno[3,2-c]pyrazole-1,5-dicarboxylate (0.071 mol, 19.1 g) in 100 mL of anhydrous dichlorometane and 114.0 mL of pyridine (1.412 mol). The resulting suspension was stirred at 5° C., for 5 hours. The crude was concentrated under vacuum and diluted with dichloromethane. The organic layer was washed with hydrochloric acid 1. N, sodium hydroxide 1 N, brine and dried over Na2SO4. The filtrate was evaporated to dryness to give a yellow solid, which was purified by flash chromatography, over silica gel, using hexane/ethyl acetate (4:1) as eluent, to afford the title compound as a pale yellow solid (19.6 g, 68%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[O:21]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]([NH:26][N:27]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:25])=[O:21]
Reactant: NNC(=O)CNC(=O)NCc1ccco1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CNC(=O)NCc1ccco1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-(2-furylmethyl)-N′-(2-hydrazino-2-oxoethyl)urea. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 71 mg of the title compound (71%) as a yellow solid in 95.6% purity by HPLC (Rt: 4.26, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:11])=[CH:21][CH:22]=1
Reactant: O=C1NCc2c(Br)cccc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Temperature: 90 °C
Reaction time: 19 h
Yield: 59.1 %

Procedure:
A suspension of Example 1C (2 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)aniline (2.5 g, 11.3 mmol), and Na2CO3 (2.2 g, 20.8 mmol) in DME (68 mL) and water (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (1 g, 0.9 mmol), and stirred at 90° C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated to one-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), and filtered. The filter cake was washed with water and ethyl acetate and dried to give 1.25 g of the desired product. MS (ESI(+)) m/e 225 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:16]=O.Cl>CN(C=O)C>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C:11](=[CH2:16])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: C=O
Agent: Cl
Solvent: CN(C)C=O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Accordingly, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one was synthesized from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one using a formaldehyde reagent (paraformaldehyde), a mineral acid (HCl), and an ammonium salt (ammonium chloride) in an aprotic solvent (DMF). The ammonium salt appears to have had a positive impact on the rate of the reaction.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH2:19]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH3:21]>CC(C)=O.CN(C=O)C>[C:23]1([N:22]([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[CH2:19][CH2:20][CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCCNc1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: CCCN(c1ccccc1)c1nc(=O)c2cccnc2s1
Yield: 80.5 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.763 g (11.2 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 894 mg of ammonium thiocyanate, 15 ml of acetone, 1.59 g of N-propylaniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 2.68 g of 2-(N-phenyl-N-propylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[NH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH3:34]>C(C(C)=O)C.C(OCC)C>[ClH:3].[CH2:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][NH:26][C:9](=[O:11])[C:8]1[C:12]([O:15][CH3:16])=[CH:13][CH:14]=[C:6]([Br:5])[C:7]=1[O:17][CH3:18])[CH3:34]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: CCN1CCCC1CN
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Product: Cl

Procedure:
30 ml of thionyl chloride is added to 17.6 g (0.067 mol) of 3-bromo-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for 30 minutes. To the solution is added 50 ml of toluene. The solvent and excess thionyl chloride is evaporated at reduced pressure. The residue is dissolved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise while stirring to 9.23 g (0.072 mol) of 2-(aminomethyl)-1-ethylpyrrolidine in 50 ml of methyl ethyl ketone. After stirring for 30 minutes at room temperature 150 ml of ethyl ether is added. The obtained precipitate is filtered off, washed with ether and recrystallized twice from ethanol-isopropyl ether. Yield: 21.0 g, m.p. 182°-84° C. (first recrystallization). m.p. 184°-85° C. (second recrystallization).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH2:38])=[S:37])[CH3:28].[C:39]([O-])(=[O:41])C.[Na+]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:38][C:39]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:41])=[S:37])[CH3:28]
Reactant: CCc1ccccc1NC(N)=S
Reactant: CC(=O)[O-]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Na+]
Product: CCc1ccccc1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(2-ethylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.112 g, 37%): 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.07 (s, 1H), 9.39 (s, 1H), 8.16-7.98 (m, 4H), 7.66-7.59 (m, 2H), 7.59-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.31-7.19 (m, 3H), 7.10 (t, J=5.6 Hz, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.55 (q, J=7.6 Hz, 2H), 1.91-1.71 (m, 2H), 1.17-1.11 (m, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[I-].[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C#CCCCO
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
4-Iodoanisol (10 g, 42 mmol), palladium (II) chloride (0.2 g, 1.1 mmol) and triphenylphosphine (0.6 g, 2.2 mmol) were dissolved in diethylamine (100 mL) then cupper(I) iodide (0.5 g, 2.2 mmol) and 4-pentyn-1-ol (5 mL, 53 mmol) were added. The reaction mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure. Ethyl acetate (150 mL) was added to the residue and the mixture was washed with 2N HCl, brine and water. The organic fraction was isolated, dried with sodium sulfate and the solvent was removed under reduced pressure. The product 16 (7.1 g. 87%) was isolated by flash chromatography (silica gel, 1:2 ethyl acetate/hexanes) as an oily yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.88 (m, 2H), 2.53 (m, 2H), 3.72 (s, 3H), 3.74 (m, 2H), 6.83 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:17]([SH:18])=[N:16][C:15]([Cl:19])=[C:14]([Cl:20])[N:13]=1>>[Cl:20][C:14]1[N:13]=[C:12]2[N:11]=[CH:1][S:18][C:17]2=[N:16][C:15]=1[Cl:19]
Reactant: Nc1nc(Cl)c(Cl)nc1S
Reactant: CCOC(OCC)OCC
Product: Clc1nc2ncsc2nc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
To 100 ml. of triethyl orthoformate was added 9.8 g (0.05 mole) of 2-amino-5,6-dichloro-3-mercaptopyrazine. The whole was heated to boiling under reflux for 20 hours, cooled to room temperature and filtered, washed with petroleum-ether and dried to give 7.7 g. (75% yield) of the desired product, m.p. 124°-5° C.