Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CCCO2)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1nnc(NC2CCC3(CCCO3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (0.29 g) and 1-oxaspiro[4.5]decan-8-one (0.64 g) in acetic acid was added sodium cyanoborohydride (1.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 34%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC([O-])(C)C.[Na+].O=O.N#N.[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1.[CH2:50]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.C(OCC)C.C(OC(=O)C)C>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([N:60]2[CH2:61][CH2:62][N:57]([CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:58][CH2:59]2)=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
Tris-(dibenzylidene-acetone)-dipalladium (0.03 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.9 mmol) and NaOtBu (6.5 mmol) are suspended in toluene (20 ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (4.65 mmol) and 1-(benzyl)-piperazine (5.6 mmol) are added and the stirred mixture is heated under reflux for 4 hours. After cooling, a mixture of ethylacetate and diethylether is added and the mixture is filtered. Then the solvent is evaporated and the residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 105-107° C., Rf=0.67 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.C(N(CC)CC)C.[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.CO>[C:20]1([C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
L-Serine (2.10 g, 20.0 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in methylene chloride (20 mL) (Wako Pure Chemical Industries, Ltd.), and then trimethylsilyl chloride (8.9 mL) (Shin-Etsu Chemical Co., Ltd.) was added thereto, followed by reflux for 20 minutes. The mixture was returned to room temperature, and then triethylamine (10 mL) (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by reflux for 45 minutes. The mixture was ice-cooled, and then triethylamine (2.8 mL) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (5.61 g, 20.1 mmol) (Wako Pure Chemical Industries, Ltd.) were added thereto, followed by stirring at room temperature for 5 hours. An excessive amount of methanol (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=99:1 as an eluent), to thereby obtain the title compound (0.36 g, 5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CO>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: NCc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed 5-(3′-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitrile (I-148, 860 mg, 2.32 mmol), methanol (20 mL) concentrated HCl (967 uL, 11.6 mmol) and 10% Pd/C. The reaction is allowed to stir at ambient temperature for 6 hours under a hydrogen atmosphere. After filtering the mixture through Celite, the filtrate is concentrated, diluted with 0.5M HCl (20 mL) and water (20 mL) followed by extractions with ethyl acetate (2×50 mL). The organic portions were combined, dried (MgSO4), concentrated and purified by silica gel column chromatography utilizing 10% 1M NH3 in MeOH/dichloromethane as the eluent to produce 121 mg of P-596 as a pale yellow solid in 14% yield.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C@H:13]([N:19]4[CH:23]=[C:22]([CH2:24][C@@H:25]([NH:30][S:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[C:26]([O:28]C)=[O:27])[N:21]=[N:20]4)[CH2:14][CH2:15][O:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Li+].[OH-]>CO>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C@H:13]([N:19]4[CH:23]=[C:22]([CH2:24][C@@H:25]([NH:30][S:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)(=[O:32])=[O:33])[C:26]([OH:28])=[O:27])[N:21]=[N:20]4)[CH2:14][CH2:15][O:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H](Cc1cn([C@@H]2CCOc3cc(CN4CCC(F)CC4)ccc32)nn1)NS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CN5CCC(F)CC5)ccc43)nn2)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
(R)-Methyl 3-(1-((R)-7-((4-Fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoate (130. mg, 0.228 mmol), 1N LiOH (0.3 mL, 0.3 mmol) in 4 mL MeOH was stirred for 14 h at RT. The reaction mixture was then stirred at 55° C. for 24 h. The reaction mixture was cooled, concentrated and neutralized with 1N HCl. A precipitate formed that was filtered and washed with ether to afford the title compound. MS (m/z): 558.4 (m+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:30][CH2:31][CH2:32][Cl:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.89 %

Procedure:
To a suspension of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (2.17 g), K2CO3 (0.99 g) in DMF (20 mL) was added 1-bromo-3-chloropropane (0.71 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (2.18 g, 82.89%).
Reaction SMILES: [CH3:1][N:2]([CH3:55])[C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[C:13]([C:21]3[NH:26][C:25]4[C:27]5[C:28](=[N:42][N:43](CC6C=CC(OC)=CC=6)[CH:44]=5)[N:29]=[C:30]([NH:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([Cl:41])[CH:34]=5)[C:24]=4[C:23](=[O:54])[N:22]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:4]1>C(O)(C(F)(F)F)=O>[Cl:41][C:35]1[CH:34]=[C:33]([CH2:32][NH:31][C:30]2[C:24]3[C:23](=[O:54])[N:22]=[C:21]([C:13]4[CH:12]=[C:11]([S:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:55])[CH3:1])[CH2:4]5)(=[O:9])=[O:10])[CH:16]=[CH:15][C:14]=4[O:17][CH2:18][CH2:19][CH3:20])[NH:26][C:25]=3[C:27]3=[CH:44][NH:43][N:42]=[C:28]3[N:29]=2)[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(NCc3ccc(OC)c(Cl)c3)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(NCc3ccc(OC)c(Cl)c3)nc3n[nH]cc3c2[nH]1

Procedure:
A solution of (3R)-3-(Dimethylamino)-1-[[3-[5-[[(3-chloro-4-methoxyphenyl)methyl]amino]-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl]-4-propoxyphenyl]sulfonyl]pyrrolidine in TFA (4 mL) was heated at reflux for 1 h. under nitrogen. After removal of the excess TFA, the residue was purified by preparative HPLC to give the desired product (32 mg) as a TFA salt. LC: 3.12 (Gradient 2); MH+: 667.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Br)(Br)[Br:19].[OH-].[Na+].Cl>CN(C)C=O>[Br:19][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Br)c1C
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
5 g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 40 ml of N,N-dimethylformamide and the resulting suspension was warmed to 65° C. 8.1 g(30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react at 75° C. for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500 g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again to pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100 ml of water and the dried to obtain 4.1 g of the title compound.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[C:8](=[O:27])[N:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=3)[C:10]3[N:11]([CH:14]=[CH:15][N:16]=3)[C:12]=2[N:13]=1)=O.[NH2:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]3([CH2:47][CH2:46]3)[CH2:34][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C>[O:27]=[C:8]1[C:7]2[CH:6]=[N:5][C:4]([NH:28][C:29]3[CH:38]=[C:37]4[C:32]([C:33]5([CH2:46][CH2:47]5)[CH2:34][N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:36]4)=[CH:31][CH:30]=3)=[N:13][C:12]=2[N:11]2[CH:14]=[CH:15][N:16]=[C:10]2[N:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C2(CC2)C1
Reactant: C=CCOc1ccc(-n2c(=O)c3cnc(S(C)=O)nc3n3ccnc23)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOc1ccc(-n2c(=O)c3cnc(Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC54CC4)nc3n3ccnc23)cc1
Temperature: 60 °C

Procedure:
To a solution of Example 205E (125 mg, 0.328 mmol) in 4 mL acetonitrile was added tert-butyl 7′-amino-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-carboxylate (108 mg, 0.393 mmol). The reaction was heated to 60° C. overnight, cooled, diluted with ethyl acetate, washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by chromatography with an Analogix 280 with an SF 24-40 column, 20% to 100% ethyl acetate/hexane gradient over 30 minutes to provide the title compound. MS (ESI+) m/z 592.36 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[CH2:31].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:31]=[CH:30][C:32]2[S:36][CH:35]=[N:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cncs1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cncs3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C

Procedure:
A pressure vessel is charged with 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (828 mg, 1.52 mmol), 5-vinyl thiazole (186 mg, 1.68 mmol), triethylamine (0.32 mL, 2.28 mmol) and tri-o-tolylphosphine (37 mg, 0.12 mmol) in CH3CN (1.5 mL). The vessel is degassed and palladium(II) acetate (6.80 mg, 0.03 mmol) is added. The vessel is sealed and heated at 80° C. for 20 h. The reaction mixture is concentrated and dissolved in EtOAc, washed with 1N HCl , dried over MgSO4 and concentrated. The residue is purified by column chromatography to afford the title compound as a yellow solid; (M+H)+=528.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([CH:10]([CH3:12])[CH3:11])[C:3]1=[O:13].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][NH2:54]>ClCCl>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][NH:54][C:7]([CH:6]1[CH2:5][N:4]([CH:10]([CH3:12])[CH3:11])[C:3](=[O:13])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CC(C)N1CC(C(=O)O)N(C)C1=O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CC(C(=O)NCc2ccc(Cl)cc2Cl)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
A mixture of 3-methyl-1-(1-methylethyl)-2-oxo-4-imidazolidinecarboxylic acid (100 mg, 0.537 mmol), N-ethylmorpholine (0.274 ml, 2.148 mmol), 1-hydroxybenzotriazole hydrate (99 mg, 0.644 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (124 mg, 0.644 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (95 mg, 0.537 mmol) in dichloromethane (1 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 ml) and the mixture was washed with saturated sodium hydrogen carbonate solution (10 ml) and brine (10 ml), dried and evaporated. The residue was purified by mass-directed automated HPLC. The residue was triturated with ether and the resulting solid was collected and dried to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-(1-methylethyl)-2-oxo-4-imidazolidinecarboxamide (124 mg, 67%). LCMS [M+H]+=344, retention time=2.32 minutes.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:6][C:5]1=S.[O:24]1CCOCC1.[K]>C(O)=O.O>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:24]
Reactant: FC(F)(F)CN1C(=S)NC(c2ccccc2)c2cc(Cl)ccc21
Reactant: C1COCCO1
Agent: [K]
Solvent: O=CO
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinethione in 50 ml. of dioxane was added dropwise a solution of 3 g of potassium permangenate in 20 ml. of water. The mixture was stirred at room temperature for 2 hours and then a few drops of formic acid was added. The resultant brown precipitate was filtered off and washed with chloroform. The filtrate was concentrated under reduced pressure and the residue was dissolved in 30 ml. of chloroform. The chloroform solution was combined, washed successively with dilute sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 184.0°-185.0° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1)#[N:2].[H][H]>[Ni].CO>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CN)cc1F

Procedure:
The catalyst (0.151 g Raney nickel), N-(4-cyano-2-fluoro-phenyl)-methane sulphonamide (1.15 g) and methanol (25 ml) were placed in a hydrogenator. The mixture was stirred over night under hydrogen at a pressure of 2 bar. 0.26 ml hydrogen was taken up. The reaction mixture was drawn off through the filtering material and the filter cake was washed with methanol. The solvent was removed under vacuum and the residue was dried. The desired product was obtained in the form of a solid (476 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)CO)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.96 g, 77%) as an off-white solid. MS (ISP) 272.2 [(M+H)+], mp 101° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)OCc3ccccc3)cc21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonylindole-6-carboxylate (450 mg) in 5.0% formic acid-methanol (10.0 ml) was added 10% palladium on carbon (153 mg) and the mixture was stirred under nitrogen atmosphere at ambient temperature for 4 hours. The resulting solution was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the solution was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether:n-hexane (1:5) to give 1-tert-butoxycarbonylindole-6-caroxylic acid (302 mg).
Reaction SMILES: [CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[O:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]1=[O:25].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:7]1[N:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]([OH:25])=[O:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2ccccc2[nH]1
Reactant: O=C1CCCC(=O)O1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2ccccc2n1C(=O)CCCC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-hexyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[Na+].[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[CH3:8].ClC(OCC)=O>O>[CH3:6][N:7]([CH3:8])[CH2:9][C:10]1[O:14][C:13]([CH2:15][S:16][CH2:17][CH2:18][N:19]=[C:1]=[S:3])=[CH:12][CH:11]=1
Reactant: S=C=S
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.5 h

Procedure:
Carbon disulphide (1.52 g) was added with stirring to a cooled solution of sodium hydroxide (0.8 g) in water (1.7 ml). 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (4.26 g) was added slowly and when addition was complete the mixture heated at 100° for 2 hr. After cooling to below 40° ethyl chloroformate (1.94 ml) was added and stirring continued for a further 30 mins. The lower thick yellow oil was extracted with chloroform, dried and evaporated to give N,N-dimethyl-5-[[[2-(isothiocyanato)ethyl]thio]methyl]furanmethanamine as an oil RF 0.43 (silica/methanol).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:42])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:14]([Cl:42])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COCCOCOc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A solution of 3 g (8.3 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid in 50 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 1.7 ml (8.3 mmol) of dicyclohexylamine was added and the mixture was stirred for one hour. 600 μl (8.3 mmol) of thionyl chloride were then added and the mixture was stirred for one hour. It was evaporated to dryness, the residue was taken up in anhydrous ethyl ether, the dicyclohexylamine salt was filtered off and the filtrate was evaporated. 3.3 g (100%) of the crude acid chloride, which was used without further purification for the remainder of the synthesis, were recovered.