Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH:59]([CH3:61])[CH3:60])=[C:57]=[O:58].N(CC)=C=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)([CH3:61])[CH3:60]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)O[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg), 4-dimethylamino-pyridine (DMAP, 1 mg) and triethylamine (30 μL) are dissolved in tetrahydrofurane (1 mL), treated with 2-isocyanatopropane (14 μL) and stirred for 12 hours. Triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. Again triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is used directly in the next step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:3]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC1CCCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH3CN (45 mL) was treated with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K2CO3 (828 g, 6 mmol) and heated to 70° C. for 9 h. The reaction mixture was cooled to 25° C. and concentrated to afford a yellow solid. The residue was partitioned between H2O (5 mL) and EtOAc (50 mL), and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated. The resulting yellow oil was purified by chromatography (SiO2, 5-20% CH3OH—CH2Cl2 gradient elution) to afford the desired product as a yellow oil (639 mg, 93%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:28]C(=O)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Yield: 98.5 %

Procedure:
To acetic acid 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (2.7 g, 5.4 mmol) in tetrahydrofuran (88 mL) and methanol (30 mL) at room temperature was added dropwise an aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h the reaction mixture was concentrated under reduced pressure. The resulting residue was combined with water (200 mL) and acidified with 10% aqueous hydrochloric acid to a pH of 1. The solution was extracted with diethyl ether (300 mL) and the diethyl ether layer was washed twice with water and dried (Na2SO4). Concentration under reduced pressure gave the title compound as a white solid (2.4 g, 100%): (DMSO-d6): δ9.54 (s, 1H), 8.16 (d, 1H), 7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.03 (s, 1H), 6.93 (m, 2H), 3.32 (m, 1H), 2.41 (s, 3H), 1.94 (m, 2H), 1.58 (s, 3H), 1.72-1.42 (m, 6H); MS(EI): [M+], 1 bromine isotope pattern, 450/452; Anal. Calc. for C25H23BrOS: C, 66.52; H, 5.13; N, 0.00. Found: C, 67.17; H, 5.25; N, 0.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].CCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)[C@@H](O)c2ccccc2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (2 mL) was added a mixture of (+)-mandelic acid (148 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added hexane/IPE at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.55 g).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:21][CH3:22])=[N:10][CH:11]=[C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([C:8]1[C:9]([O:21][CH3:22])=[N:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cnc(OC)c(Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(OC)c(Cc2ccccc2)c1
Yield: 99.3 %

Procedure:
A mixture of 950 mg of 3-benzyl-5-(2-ethoxycarbonylethenyl)-2-methoxypyridine, 90 mg of 10% palladium carbon and 10 ml of ethanol was stirred at room temperature for one hour in a hydrogen atmosphere. After the atmosphere in the system was replaced by nitrogen, the mixture was filtered through Celite. The solvent was removed, to give 950 mg of the target compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:6][CH2:5]1)[CH2:30][CH2:31][CH3:32]
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2cc(N3CCOCC3)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine (14 mg, 0.0363 mmol) produced in Example (81e), butyraldehyde (0.0097 mL, 0.109 mmol) and tetrahydrofuran (0.5 mL) was added sodium triacetoxyborohydride (23 mg, 0.109 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled of by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4-[3-(4-butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:32](O)=[O:33].CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:32]([C:31]4[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:29]([OH:28])[CH:30]=4)=[O:33])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(C(=O)O)cc1O
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (164 mg, 0.4 mmol), 3-hydroxy-4-(methoxycarbonyl)benzoic acid (78 mg, 0.4 mmol), EDCI (153 mg, 0.8 mmol) and N-methylimidazole (100 mg, 1.2 mmol) in 5 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (4 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, 100% DCM to DCM:MeOH=50:1) to give methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate (100 mg, yield 45%). LC-MS: 551 [M+H]+, tR=1.61 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([OH:8])=O)[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:41][CH2:42][C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([NH:48][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([C:42]#[N:41])=[CH:44][CH:45]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)C(=O)NCc1ccc(C#N)cc1
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A solution under N2 of (RS)-2-ethoxy-malonic acid monoethyl ester (666 mg, 1.0) in THF (37 ml) was prepared. BOP (2.17 g), 4-aminomethyl-benzonitrile hydrochloride (555 mg) and N-ethyldiisopropylamine (733 mg) were added at 0° C. The ice bath was removed and the reaction was let to stir 24 h. THF was evaporated and the mixture was diluted with EtOAc. This organic phase was washed with a sat. aq. NaHCO3 sol. and with brine. The aqueous phases were extracted with one more portion of EtOAc and dried over MgSO4. The solvent was evaporated. The crude product was purified by flash chromatography. (heptane/EtOAc 3:1 to 2:1). 750 mg (68%) of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid ethyl ester were isolated as a yellow oil. MS 308.4 (100, [M+NH4]+), 291.1 (88, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:6]=1.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:37])=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:33])[F:34])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Reactant: CB1OB(C)OB(C)O1
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: COCCOC
Product: COC(=O)Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.20 g, 0.35 mmol), trimethylboroxine (0.07 mL, 0.53 mmol), potassium carbonate (0.123 g, 0.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 0.035 mmol) were combined in DME:H2O (2:1; 4 mL) and degassed with N2 for 8 minutes. The reaction was stirred at 90° C. for 2 hours, and then worked up with EtOAc and 10% aqueous HCl. The residue was purified by silica gel chromatography to give {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:18](=O)[CH2:19][CH2:20][C:21]=2[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li][CH3:26]>>[CH3:22][C:21]1[CH2:20][CH:19]=[C:18]([CH3:26])[C:17]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:24])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: [Li]C
Reactant: CC1=C(c2ccccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1
Product: CC1=CCC(C)=C1c1ccccc1NS(=O)(=O)c1ccc(C)cc1

Procedure:
The same experiment as in Example 17 was carried out, using 1.000 g (2.93 mmol) of 2-(2-(p-toluenesulfonyl)aminophenyl)-3-methyl-2-cyclopenten-1-one and 3.660 ml (5.860 mmol) of MeLi (1.6 M in diethyl ether) (0.617 g, 62%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Mg]Br)[CH3:18].[Mg].C(Br)C.[Cl-].[NH4+]>CCOCC>[CH2:17]([C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:18]
Reactant: CC[Mg]Br
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC1(O)c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5H-dibenzo[a,d]cyclohepten-5-one (15.5 g., 0.075 mole) is added in portions to a solution of ethyl-magnesium bromide, prepared from 3.64 g. (0.15 mole) of magnesium and 16.4 g. of ethyl bromide in ether. After stirring for one hour at room temperature, the mixture is heated to refluxing for 15 minutes, then cooled, and the Grignard adduct is hydrolyzed by cautiously adding ammonium chloride solution. The crude 5-ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptane is recovered from the ether layer in a yield of 16.78 g. (95%), m.p., 63°-65° (clearing at 70°C.). After recrystallization from petroleum ether, hexane and finally isopropyl alcohol, an analytical sample melted at 63°-65°C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:5]([OH:7])=[O:6])C.[CH3:8][C:9]([NH:12][CH2:13][C@H:14]([OH:28])[CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1)([CH3:11])[CH3:10].[OH2:29]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:11][C:9]([NH:12][CH2:13][C@H:14]([OH:28])[CH2:15][O:16][C:17]1[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:19][S:20][N:21]=1)([CH3:8])[CH3:10].[CH:3](/[C:5]([OH:7])=[O:6])=[CH:2]/[C:1]([OH:16])=[O:29]
Reactant: CCC(C)C(=O)O
Reactant: O
Agent: CC(=O)[O-]
Agent: CC(C)(C)NC[C@H](O)COc1nsnc1N1CCOCC1
Agent: [Zn+2]
Product: O=C(O)/C=C\C(=O)O

Procedure:
15 grams of Carbopol 974P is dispersed in 40 grams of heavy mineral oil USP and is added to 841.5 grams of water containing 2.5 grams of timolol meleate with vigorous stirring. 100 grams of water containing 1.0 gram of zinc acetate is added in a controlled fashion with homogenization to get a particle size distribution size below 5 micron.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:18][CH:17]=1)#[N:2].[OH-:32].[Na+].Cl>CS(C)=O>[NH:25]([C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]([NH2:2])=[O:32])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [OH-]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C(N)=O
Reaction time: 2 h

Procedure:
The N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-phenylurea (100 mg) synthesized in Example 37 was dissolved in dimethylsulfoxide (3 ml) at 80° C., and then 5N aqueous sodium hydroxide was added and the mixture was heated and stirred for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and the precipitated crystals were filtered out and washed with ethanol to obtain the title compound (60 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:23][C:22]#[CH:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is alkylated using 3-bromo-propyne and K2CO3. After aqueous work-up the crude material (5.11 g) is de-acetylated in MeOH (180 ml) using DBU (1,3 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-prop-2-ynyl-1,3-dihydro-indol-2-one (4.32 g) is obtained and used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32](OC)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]>C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]
Reactant: COC(=O)c1cc(CC(C)C)c(C(=O)OC)nn1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Temperature: 25 °C
Yield: 54.5 %

Procedure:
An oven dried, nitrogen cooled two-necked 25 mL round bottom flask was charged with a solution of 78 μL piperidine (0.793 mmol, 68 mg) in 4.0 mL anhydrous DCM. Trimethyl aluminum was added slowly (2.0M/toluene, 436 μL, 0.872 mmol). The resulting mixture was stirred for twenty minutes at room temperature. To this solution was added 200 mg of the diester 3 (0.793 mmol) dissolved in 2.0 mL anhydrous DCM. The flask was sealed and heated to 41° C. for 15 hours. The reaction was allowed to cool to room temperature and quenched with slow addition of 1M HCl. The product was extracted three times with DCM, the organic fractions collected, washed with brine, dried over magnesium sulfate and evaporated to give a brownish/yellow oil. The crude mixture was applied to a column of silica gel and eluted with a 2:1 hexane-ethyl acetate solution (Rf=0.16) to give 132 mg of product (54% yield) as a yellow oil. MS: (ESI-TOF) MH+ expected: 306.1812, found: 306.1807.
Reaction SMILES: [Na+].[SH2:2].Br[CH2:4][CH2:5][O:6][CH3:7]>>[CH3:7][O:6][CH2:5][CH2:4][S:2][S:2][CH2:4][CH2:5][O:6][CH3:7]
Reactant: S
Reactant: COCCBr
Agent: [Na+]
Product: COCCSSCCOC
Temperature: 23.5 °C

Procedure:
To 8 mL of the sodium polysulfide solution of Example 1 was added 1-bromo-2-methoxy ethane (3.7 g) with stirring at 22-25° C. Extraction of the reaction mixture with ether, washing of the ethereal solution with water, and concentration gave an oil. Distillation of the oil yielded 1.0 g of bis(methoxyethyl)disulfide. Analysis of the oil gave the following results: C, 38.27%; H, 7.82%; S, 36.18%. Calculated for C6H14O2S2: C, 39.56%; H, 7.69%; S, 35.16%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:30]3[CH2:31][CH2:32][C@H:28]([F:27])[CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: F[C@H]1CCNC1
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: F[C@H]1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (90 mg, 0.2 mmol) in dry CH2Cl2 (2 mL) was added to (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol), DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for 2 days. Further CH2Cl2 (3 mL), (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol) and DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for an additional 7 days. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane), followed by preparative HPLC to provide Compound IIt as a white solid (25 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12](=[S:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.C(O)C>[C:5]1([C:3]2[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:18][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C(N)=S
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (1.790 g, 8.99 mmol) and ethyl 2-amino-2-thioxoacetate (Example 4A, 1.20 g, 9.01 mmol) in benzene (80 mL) and ethanol (10 mL) was stirred at room temperature for 18 h. The mixture was heated at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual clear oil was chromatographed on silica gel (4×10 cm, elution toluene-ethyl acetate 0-2-4%) and gave a yellow oil (1.588 g). This was distilled in vacuo (bp: 105-115° C./0.1 torr, bulb to bulb distillation, air bath temperature) to provide the title material (1.409 g, 67%) as a pale yellow syrup which solidified to an almost colorless solid upon standing. LC (Method C): 2.009 min. HRMS (ESI) calcd for C12H12NO2S [M+H]+ m/z 234.0583. found 234.0597. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.48 (t, J=7.2 Hz, 3H), 4.52 (q, J=7.2 Hz, 2H), 7.35-7.49 (m, 3H), 7.75 (s, 1H), 7.93-8.00 (m, 2H).