Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.CC#N.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:29][CH2:30][O:31][CH3:32])(=O)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:29][CH2:30][O:31][CH3:32])[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC1(C)CCn2c(nc(Cl)cc2=O)N1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Temperature: 65 °C
Yield: 70.4 %

Procedure:
0.19 g of 2-chloro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are suspended in 7 mL de CH3CN, 0.58 g of cesium carbonate and 0.27 g of 2-methoxyethyl methanesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel SiO2 (CH2Cl2/MeOH, 99/1). 0.17 g (yield=50%) of 2-chloro-9-(2-methoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a brown powder including the following characteristics:
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH:8]([F:10])[F:9])(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:43][C:24]3([CH2:29][CH2:28][N:27]([C:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([CH3:42])[CH:33]=4)=[O:31])[CH2:26][CH2:25]3)[CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:43][C:24]3([CH2:25][CH2:26][N:27]([C:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:40])[CH3:41])=[C:34]([CH3:42])[CH:33]=4)=[O:31])[CH2:28][CH2:29]3)[CH2:23][N:22]([CH2:7][CH:8]([F:10])[F:9])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)F)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Temperature: 70 °C
Yield: 106.5 %

Procedure:
2,2-difluoroethyl trifluoromethanesulfonate (17 mg, 0.08 mmol) was added to a solution of [10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (22 mg, 0.05 mmol) and NaHCO3 (13 mg, 0.15 mmol) in anhydrous ethanol (0.3 mL) at room temperature. The reaction mixture was purged with argon, sealed with a cap and heated at 70° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with MeOH to 1 mL, microfiltered and purified by Waters mass directed LC/MS: (10-99% ACN/H2O (5 mM HCl)) to yield [10-(4-chlorophenyl)-8-(2,2-difluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (27 mg, 100%). ESI-MS m/z calc. 506.21478. found 507.2 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].CO>C(Cl)Cl.CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CCN(C)C

Procedure:
Method I was used with ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (124 mg, 0.632 mmol), caesium carbonate (624 mg, 1.915 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (96.8 mg, 0.672 mmol). 48 hours reaction time. Column eluent: 50→100% EtOAc in CH2Cl2, followed by 0→10% MeOH in EtOAc. Yield: 103 mg (61%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 2-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 445.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30](O)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 48 h
Yield: 42.1 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.00 g, 8.70 mmol) was dissolved in dimethylformamide (150 ml). To the obtained solution, carbobenzyloxy-L-proline (2.80 g, 11.3 mmol), WSC-HCl (2.00 g, 11.3 mmol) and HOBT (1.53 g, 11.3 mmol) were added, and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was condensed under reduced pressure. The resultant residue was extracted using a solvent mixture (chloroform: methanol=4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=20:1). The crude crystals were subjected to a recrystallizing procedure using chloroform--methanol--ether. As a result, 1.69 g of the title compound was obtained as colorless powdery crystals (42.1%).
Reaction SMILES: C(N=C=O)CCCCC[N:7]=C=O.[C:13]([O:17][CH2:18][CH2:19]O)(=[O:16])[CH:14]=[CH2:15]>>[NH2:7][C:13]([O:17][CH2:18][CH3:19])=[O:16].[C:13]([O-:17])(=[O:16])[CH:14]=[CH2:15]
Reactant: O=C=NCCCCCCN=C=O
Reactant: C=CC(=O)OCCO
Product: C=CC(=O)[O-]
Product: CCOC(N)=O

Procedure:
Adipic acid was reacted with 1,6-hexanediol to produce a polyester polyol resin. The resulting polyester polyol resin was reacted with hexamethylene diisocyanate and 2-hydroxyethyl acrylate to produce a urethane-acrylate resin.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][Br:34])[C:27]([OH:29])=O)[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:46][S:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:59]([NH2:60])[C:58](=[O:61])[N:53]2[C:54]=1[C:55]([OH:57])=[O:56]>C(O)=O>[CH3:46][S:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:59]([NH:60][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH2:20])[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][Br:34])[C:58](=[O:61])[N:53]2[C:54]=1[C:55]([OH:57])=[O:56]
Reactant: O=C(O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=CO
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCBr)c3csc(N)n3)[C@H]2SC1

Procedure:
Using the procedure of Example 17, 1.909 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetic acid (described in French Pat. No. 2,438,050), 0.68 g of tosyl chloride, 0.927 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid and 15 ml of 67% aqueous formic acid were reacted to obtain 0.615 g of pure syn isomer of 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-bromoethoxyimino}-acetamido]-ceph-3-eme-4-carboxylic acid with a melting point of 185° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1.O1CCOCC1>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.O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cncc(F)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 46 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (300 mg, 0.63 mmol, prepared as described in Method BB26), potassium carbonate (437 mg, 3.16 mmol), 5-fluoropyridin-3-ylboronic acid (178 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (73.1 mg, 0.063 mmol), dioxane (4.22 mL) and water (2.12 mL). The reaction was stirred and heated at 100° C. for 1 h. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (24 g), 0-50% EtOAc in hexanes to provide a white solid, (S)-3-bromo-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (130 mg, 0.29 mmol, 46%). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(Cl)Cl.CCOC(C)=O.CC(O)=O>[CH2:14]([O:13][C:9](=[O:12])[CH2:10][N:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: CCOC(=O)C=O
Reactant: NCCc1cccs1
Reactant: CCOC(=O)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CCc1cccs1)C(=O)OCC
Reaction time: 0.33 h

Procedure:
2-Thiophen-2-yl-ethylamine (21.0 g, 165 mmol) was stirred in 1 liter of DCM. Ethyl glyoxylate (165 mmol, 50% in toluene) was added followed by 50 uL HOAc. The reaction was stirred for 10 minutes after which time NaBH(OAc)3 (214 mmol, 45 g) was added slowly. After 15 minutes HOAc was added (214 mmol) and the reaction was stirred for 20 minutes. The reaction was concentrated and the crude material was redissolved in 500 mL each of THF and water. NaHCO3 (42 g, 500 mmol) was added followed by ethyl chloroformate (21 mL, 214 mmol). Saturated NaHCO3 was added slowly to the reaction until the gas evolution was minimal. After stirring overnight, the reaction was diluted with EtOAc (400 mL). The product was extracted 2× into EtOAc, dried over MgSO4 and concentrated to the sub-title product as a dark oil.
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([CH3:11])([CH3:10])[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]1N1CCCCC1)[CH:2]=[CH2:3].C([O-])(=[O:22])C.[Na+].C(=O)(O)[O-].[Na+].N>C(O)(=O)C.O>[CH2:1]([CH:4]1[C:5](=[O:22])[CH2:6][C:7]([CH3:13])([CH3:12])[NH:8][C:9]1([CH3:11])[CH3:10])[CH:2]=[CH2:3]
Reactant: CC(=O)[O-]
Reactant: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1C(=O)CC(C)(C)NC1(C)C
Reaction time: 8 h

Procedure:
1.46 g of the 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine thus obtained were dissolved in a mixture of 3 ml of acetic acid, 1.5 g of sodium acetate and 3 ml of water, and the solution was allowed to stand overnight. To the solution were then added 6.0 g of sodium bicarbonate and 3 ml of concentrated aqueous ammonia; the solution was then extracted with hexane. The hexane extract was dried over magnesium sulphate and then treated with charcoal giving, after removal of the hexane, 0.91 g of 3-allyl-2,2,6,6-tetramethyl-4-piperidone. On thin layer chromatography using a 0.25 mm thick layer of alumina and a mixture of benzene, hexane, ethyl acetate and triethylamine (2 : 2 : 1 : 0.5 by volume) as developing solvent, the compound showed a single spot having an Rf value of 0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17]1=[O:34])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:35](=O)([O-])[O-].[Na+].[Na+]>C=O.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([N:21]([CH3:35])[CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:17]1=[O:34])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN(C1CCN(c2ccncc2)CC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
(3S)-3-(6-Chloronaphthalene-2-sulfonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-pyrrolidone (400 mg) was dissolved in a 37% aqueous solution of formaldehyde (11 ml) and formic acid (5 ml) and refluxed for 3 hours. The reaction mixture was cooled and made alkaline by adding an aqueous solution of sodium carbonate, extracted with dichloromethane, dried and concentrated. The residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from dichloromethane to obtain the title compound (180 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.Cl.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:29][CH2:28]1.C(Cl)[Cl:40]>CO.C(Cl)(Cl)Cl>[ClH:40].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:30]3[CH2:29][CH2:28][O:27][CH2:32][CH2:31]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: ClCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
6.4 g. (18.7 mmole) of 4,4-Dimethyl-9-hydroxy-7-(3methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l] benzopyran, 4.33 g. (21.0 mmoles) of cycyclohexylcarbodiimide and 4.26 g. (20.3 mmoles) of γ-morpholinobutyric acid hydrochloride were combined with 325 ml. of methylene chloride and stirred at room temperature for a total of 24 hours. The insoluble by-product of dicyclohexylurea was separated for filtration and the methylene chloride was removed using a rotary evaporator. The brown viscous residue was dissolved in about 100 ml. of benzene and the benzene solution was filtered to remove a small amount of insoluble material. The benzene was removed using a rotary evaporator and the remaining residue was triturated with approximately 250 ml. of ether. The solid which formed was filtered, washed with ether and dried to give 8.6 g. of beige solid. The material was crystallized from benzene/ether to give 3.5 g. of product as a colorless solid, m.p. 151°-153°. The material was pure by thin layer chromatography (10% MeOH/CHCl3); the infrared and nmr spectra are in agreement with the proposed structure. An additional 3.3 g. of somewhat impure material was recovered from the mother liquor.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:41])[CH:13]=2)(OC(C)(C)C)=O.C([CH:49]([NH2:56])[CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1)(OC(C)(C)C)=O>>[Cl:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH2:49][NH2:56])[CH2:51]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Reactant: CC(C)(C)OC(=O)C(N)C1CCCNC1
Product: NCC1CCCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1
Reaction time: 8 h
Yield: 99 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-dichloro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-(Boc-aminomethyl)piperidine. The reaction can be completed at room temperature overnight 1H-NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 2H), 8.34 (s, 1H), 8.08 (s, 2H), 7.40-7.31 (m, 4H), 4.35 (t, J=5.6 Hz, 2H), 3.35-3.20 (m, 2H), 2.89-2.75 (m, 2H), 2.70-2.53 (m, 2H), 2.18-1.71 (m, 9H), 1.17-1.03 (m, 2H); MS (ESI) m/z 493.2 (M−H)−; MS (ESI) m/z 495.1 (M+H)+
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:19][NH:20][C:21]([NH2:23])=[S:22].O>C(O)C>[CH3:19][NH:20][C:21]1[S:22][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:23]=1
Reactant: CNC(N)=S
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 80.9 %

Procedure:
A solution containing 32.4 g (0.10 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide and 11.3 g (0.13 mole) of N-methylthiourea in 250 ml of ethanol was refluxed for four hours. The reaction mixture was poured into 700 ml of water and ethanol was added. A small quantity of insoluble material was removed by filtration and the filtrate was made strongly alkaline by the addition of ammonium hydroxide. The solution was cooled and an additional 400 ml of water was added. The precipitated solid was collected and dried in an oven. There was obtained 25.5 g (81%) of product, m.p. 153°-55°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8-2.9 (CH3, doublet), 3.5 (CH2), 6.3 (hetero-aromatic), 7.3-8.1 (aromatic, NH), 10.4 (HNC=0).
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:5]=2[S:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.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>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])/[CH:12]=[CH:11]/[C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)[C:6]=2[C:7]([NH2:20])=[N:8][CH:9]=1)[CH3:16]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
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: COCCOC
Solvent: O
Product: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of Example 176A (250 mg, 0.70 mmol), 4-phenoxyphenylboronic acid (180 mg, 0.84 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), and sodium carbonate (150 mg, 1.4 mmol) in 1,2-dimethoxyethane (8 mL) and water (4 mL) was heated to reflux for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (170 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 8.00 (s, 1H), 7.56 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.13 (m, 4H), 6.81 (d, 1H), 6.17 (dd, 1H), 5.67 (br s, 2H), 5.13 (d, 1H), 3.57 (m, 4H), 1.18 (t, 6H); MS m/e 447.3 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][N:38]([C:9]([C:8]4[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=4[O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:11])[CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(S(=O)(=O)c4ccccc4)s3)CC2)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 4(d)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 57%). MS (m/e): 576.0 (M+H+, 100%), 593.3 (M+NH4+, 94%).
Reaction SMILES: [CH3:1][S:2][C:3]1C=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][N:4]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.[Cl-].[NH4+:17]>O1CCCC1>[CH:11]1([CH:9]([C:6]2[CH:7]=[N:17][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[OH:10])[CH2:13][CH2:12]1
Reactant: [NH4+]
Reactant: CSc1ccc(C=O)cn1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)C2CC2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of 2-(methylthio)pyridine-5-carbaldehyde (2000 mg, 12.97 mmol) in tetrahydrofuran (20 mL) was added a solution of 0.5 mol/L cyclopropylmagnesium bromide in tetrahydrofuran (28.6 mL) at −40° C. under argon atmosphere. The reaction solution was stirred at the same temperature for 10 minutes, and then slowly warmed to 0° C. and stirred for 1 hour. To the reaction solution was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→60:70) to give cyclopropyl[2-(methylthio)pyrimidin-5-yl]methanol (822 mg, 32%) as a colorless oil.