Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3](=[S:5])=[S:4])[CH3:2].[CH3:6][C:7]([CH3:11])([SH:10])[CH2:8][CH3:9].C(N(CC)CC)C>O1CCCC1>[CH3:6][C:7]([S:10][P:3]([CH2:1][CH3:2])([SH:5])=[S:4])([CH3:11])[CH2:8][CH3:9]
Reactant: CCC(C)(C)S
Reactant: CCP(=S)=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)SP(=S)(S)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 16.5 grams (g) of ethylthionophosphine sulfide in tetrahydrofuran, under nitrogen at room temperature, was added 13.8 g (0.133 mole) 1,1-dimethyl-1-propanethiol (tertiary amyl mercaptan). To this mixture was added 18.5 milliliters (ml) (0.133 mole) triethylamine, dropwise. The mixture was stirred one hour at room temperature, then refluxed for 1/2 hour and stripped of solvent. There was obtained 30.1 g (87% of theoretical yield) of the triethylamine salt of S-(1,1-dimethylpropyl)ethylphosphonotrithioic acid).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28]>>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:22])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNCCCN(C)C
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(N(C)CCCN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (200 mg, 0.67 mmol) and N,N,N-trimethyl-1,3-propane diamine (116 mg, 1.0 mmol) by a procedure similar to Example 1 and was isolated as a brown oil (112 mg, 44%). 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 6.9 (m, 3H), 6.6 (m, 1H), 3.81 (s, 3H), 3.78 (t, 2H), 3.5 (s, 3H), 3.48 (s, 3H), 3.3 (s, 3H), 2.4 (m, 2H), 2.2 (s, 3H), 1.8 (m, 2H); LC-MS (ESI+; 380 ([M+H]+)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([F:19])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[C:12]([F:19])[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(F)c1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F)C2
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-fluoro-benzoic acid from Example E2 (1.35 g, 5.0 mmol), 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (11.0 g, 5.0 mmol) and PyBroP (3.03 g, 6.5 mmol) in dichloromethane (25 ml) and DIEA (1.31 ml, 7.5 mmol) was heated at reflux for 18 h. After cooling to room temperature, the mixture was washed with 5% KHCO3, 1M HCl then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.25 g, 56%).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+:6].[Na+].[Na+].[Cl-].[Na+].[CH2:11](O)C1C=CC=CC=1.[CH3:19][C@@H:20]([C@@H:26]1[C@@:30]2([CH3:46])[C@@H:31]([OH:45])[CH2:32][C@@H:33]3[C@@:38]4([CH3:44])[CH2:39][CH2:40][C@@H:41]([OH:43])[CH2:42][C@H:37]4[CH2:36][CH2:35][C@H:34]3[C@@H:29]2[CH2:28][CH2:27]1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH3:19][C@@H:20]([C@@H:26]1[C@@:30]2([CH3:46])[C@@H:31]([OH:45])[CH2:32][C@@H:33]3[C@@:38]4([CH3:44])[CH2:39][CH2:40][C@@H:41]([OH:43])[CH2:42][C@H:37]4[CH2:36][CH2:35][C@@:34]3([CH3:11])[C@@H:29]2[CH2:28][CH2:27]1)[CH2:21][CH2:22][C:23]([O-:25])=[O:24].[Na+:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@]3(C)CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A composition of sodium deoxycholate (0.5% and 1%) was prepared comprising sodium phosphate (10 mM), sodium chloride (75-90 mM), benzyl alcohol (0.9%), deoxycholic acid, pH 8.3.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+].Cl>CO>[C:14]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Yield: 92 %

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydride in methanol (reaction time: 5 hours) followed by purification on a silica gel column using methylene chloride/methanol =20:1. This results in a 50:50 diastereomer mixture of the base. This is recrystallised from a mixture of ether/ethyl acetate =65:10. The mother liquor resulting from this is mixed with ethereal hydrochloric acid, and the mixture is evaporated to dryness. The residue resulting from this is recrystallised from a mixture of ether/ethyl acetate/methanol =100:60:1. The mother liquor obtained after the crystals have been removed by filtration is evaporated to dryness, and the base is liberated by shaking with alkali and methylene chloride and purified on a silica gel column using methylene chloride/methanol =20:1 as eluant. This results in diastereomer B as an oil approximately 92-94% pure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26]Br)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[C:21]([CH2:26][NH:1][C:2]2[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=2[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Br)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
To a solution of isopropyl 2-(3-amino-2,4-difluoro-phenoxy)acetate (intermediate IV(b)) (350 mg, 1.43 mmol, 1.0 eq) and 1-bromo-3-(bromomethyl)-5-methyl-benzene (528 mg, 1.99 mmol, 1.4 eq) in DMSO (15 mL) was added K2CO3 (593 mg, 4.29 mmol, 3.0 eq). The reaction was heated at 100° C. for 1 h in a microwave reactor, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 100:1 to 80:1) to give the title compound as a light yellow oil (192 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[CH2:24]([C:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:30](=[O:39])[C:29]([C:40](O)=[O:41])=[CH:28][CH:27]=1)[CH3:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:29]5[C:30](=[O:39])[N:31]([C:32]6[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=6)[C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=5)=[O:41])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)c(=O)n1-c1ccc(F)cc1
Yield: 74.4 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.324 mmol), 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (101.5 mg, 0.389 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (111 μL, 0.648 mmol) and HATU (148 mg, 0.389 mmol) and in the same manner as in Example 57, the title compound (133 mg, 74%) was obtained as a white solid.
Reaction SMILES: [O:1]([C@H:8]1[C@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.O>CN(C)C=O>[O:1]([C@H:8]1[C@@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([O:20][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Oc1ccccc1)CCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OCC[C@H]1Oc1ccccc1
Reaction time: 0.33 h
Yield: 13.9 %

Procedure:
To a solution of 950 mg of the cis-title product of Example 29 in 25 ml of dimethylformamide was added 173 mg of 50% sodium hydride. After stirring for 20 minutes, 641 mg of 2-chloromethylquinoline was added. The reaction was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to afford the crude product which was purified by recrystallization from methyl acetate/hexane to afford 200 mg of title product, m.p. 130-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][NH:32][C@@H:31]([CH3:35])[CH2:30]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[F:36][C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42][CH2:43][C:44]2[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=2)=[CH:39][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:48][C:47]3[CH:50]=[CH:51][C:44]([CH2:43][CH2:42][O:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:53][CH:52]=4)=[CH:45][CH:46]=3)[C@@H:31]([CH3:35])[CH2:30]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN[C@@H](C)C4)cc3Cl)nc2)cc1
Reactant: O=Cc1ccc(CCOc2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(F)cc6)cc5)[C@@H](C)C4)cc3Cl)nc2)cc1
Yield: 61.6 %

Procedure:
To a CH2Cl2 (5 mL) solution of (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-[(3S)-3-methylpiperazin-1-yl]prop-2-en-1-one (0.50 g) and 4-[2-(4-fluorophenoxy)ethyl]benzaldehyde (298 mg) was added NaBH(OAc)3 (323 mg) at room temperature. The resultant mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 0/1) to give (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-[(3S)-4-{4-[2-(4-fluorophenoxy)ethyl]benzyl}-3-methylpiperazin-1-yl]prop-2-en-1-one as a yellow powder (451 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:55][C@H:54]([CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=1)[CH2:56][NH:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)c3c[nH]c4ccccc34)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(c1c[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(1H-indol-3-yl)methanone (Step C) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.20 g, 0.495 mmol) according to Procedure G to give the title compound (0.03 g, 0.057 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.[CH2:25](Br)[CH:26]=[CH2:27].O>C(O)C>[CH2:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: C=CCOn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a solution of 0.4 g (1.5 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 40 ml ethanol was added 20 ml 0.5 M phosphate buffer pH 7.4. The mixture was added 0.8 ml (9.3 mmol) allyl bromide, and then stirred at 25° C. for 4 h. Addition of 80 ml water gave 0.33 g (72%) 1-allyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione as a precipitate. M.p. 239° C. decomp. (methanol-water). NMR (DMSO-d6) 7.9 (1H, s), 7.6 (1H, s), 6.1 (1H, m), 5.4 (2H, m), 4.7 (2H, d).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[N+:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-])=O.[H][H]>[Pt].C1(C)C=CC=CC=1>[NH2:8][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Yield: 80.5 %

Procedure:
Platinum on carbon (1.0 g of 10%) and sodium sulfate (2 g) were added to a slurry of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl}carbamate (100 g, 0.30 mol) in toluene (500 mL). The reaction vessel was placed on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure overnight at ambient temperature. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 73 g of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate as a dark gold oil. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[BrH:13]>S(=O)(=O)(O)O>[Br:13][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12]
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: Br
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a stirred solution of 5-amino-1H-isoindole-1,3(2H)-dione (1.0 g, 6.2 mmol) dissolved in sulfuric acid solution (2 mL of Con. H2SO4 in 7.5 mL of H2O) at 0° C., was added ice cold sodium nitrite solution (0.8 g in 2 mL of H2O) dropwise. After 45 min of stirring at 0° C., CuBr (3.4 g, 23.7 mmol) and HBr[48%] (13.6 mL, 4 vol. w.r.t. CuBr) were added at the same temperature. The resulting mixture was stirred at 80° C. for 8 h then poured into crushed ice. Filtered the solid, washed with ice cold water and dried thoroughly to give 0.6 g (43.0%) of 5-bromo-1H-isoindole-1,3(2H)-dione as a brown colour solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].[F-].[Cs+]>C(#N)C>[F:21][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
Procedure EE: In a microwave reactor vessel, add (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (1.0 mmol), 4-methanesulfonylphenyl boronic acid (2.5 mmol), dichloropalladium di-triphenylphosphine (0.2 mmol), cesium fluoride (9.0 mmol) and acetonitrile (0.20M) and run in a CEM microwave reactor for 10 minutes at 120° C. with 75W power and cooling on. After this time, wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 431.2 (M+1)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O:38][C:39](=[O:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47](O)[CH3:48])=[CH:43][CH:42]=1)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C@@H:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C:39]([OH:50])=[O:38])=[CH:42][CH:43]=1)[CH3:48])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Solvent: Oc1ccccc1
Product: C[C@@H](Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of example 69 using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol as the phenol and [4-(1-Hydroxy-ethyl)-phenyl]-acetic acid ethyl ester as the alcohol and isolated using chiral column chromatography. MS (ESI) m/z 540.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])=[O:11]
Reactant: C=CCCCCCCCCOC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCCCCCCCOC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (79.8 mL of a 2.0M solution, 0.160 mol) is placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 9-Decen-1-yl acetate (14.91 g, 0.075 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 2-naphthoyl chloride (13.80 g, 0.071 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (47 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[K+].[Br-]>CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][CH2:11][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:14][CH:15]=1
Reactant: COc1ccc(SCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(SCn2cc(Cl)cnc2=O)cc1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 1-chloromethylthio-4-methoxy benzene [see Preparation 1] (10 mmol) in a manner similar to that described in Example 2. The reaction time was 2 h. Yield: 2.46 g (87%) of the N- and O-isomers in the ratio 7:5. The N-isomer was isolated by its lower solubility in methanol; m.p. 140° C. (MeOH). (Found C41.23; H4.00 Calc. for C12H11ClN2O2S: C50.97; H3.93) 1H NMR (DMSO-d6): δ 3.77 (OMe), 5.12 (CH2), 6.8-7.4 (Ph), 7.90 and 8.56 (H-4 and H-6, respectively, J 4 Hz). IR (KBr): 1660 cm-1 (CO. MS (70 eV, m/z % rel. int.)]: 282/284 (5/2,M), 143/145 (100/33).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](O)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[OH:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of borane dimethyl sulphide complex (2.85 ml, 30 mmol) in THF (50 ml) was added dropwise at 0° C. to a solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (2.43 g, 10 mmol) in THF (100 ml). The reaction mixture was stirred at 0° C. for 15 minutes and at room temperature for 3 hours, methanol was cautiously added and the mixture was concentrated. The crude product was repeatedly treated with methanol and concentrated again, and finally dried under a high vacuum. Used without further purification.