Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]2[N:16]=[C:17]([S:20][CH3:21])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:38])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH2:11][C:12]1[C:23](=[O:24])[N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:15]2[N:16]=[C:17]([S:20]([CH3:21])=[O:38])[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester (1.67 g, 3.93 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.34 g, 5.11 mmol) were dissolved in dichloromethane (20 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as a white solid (0.98 g, 56.6%). 1H NMR δ (400 MHz, CDCl3) 8.89 (s, 1H), 7.68 (s, 1H), 7.32 (m, 5H), 5.96 (m, 1H), 5.52 (t, J=6.4 Hz, 1H), 5.09 (s, 2H), 4.32 (d, J=6.3 Hz, 2H), 2.95 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.95 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: C(=O)([O-])O.[K+].C([O:14][CH2:15][C:16](=[O:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)(=O)C1C=CC=CC=1>O.CO.C(O)C>[CH2:15]([OH:14])[C:16](=[O:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)COC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Yield: 100.3 %

Procedure:
A solution containing 7.5 g of potassium hydrogen carbonate in 14 ml of water is added to the suspension containing 2.5 g (5.7 mmoles) of 4-pregnene-3,20-dione-21-ol benzoate in 100 ml of methanol and the mixture is refluxed for 3 hours. Subsequently, the solvent is evaporated and the residue is taken up in 150 ml of water. The product is extracted 3 times with 80 ml of ethyl acetate each, the organic phase is washed with water, dried and evaporated. The residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.89 g 99% yield of the aimed product, m.p.: 132°-135° C., [α]D =+175.2° (c=0.5 in ethanol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][N:32]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CN2CCOCC2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (step 3, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, morpholine (1 ml) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.60 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H); ES Mass: 283 (100%) [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:12]Br.C(OCC)C>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrBr
Reactant: COc1ccc(C#N)c(N)c1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(N)c(C#N)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Amino-4-methoxybenzonitrile (4.47 g, 30.2 mmol) is dissolved in 70 ml of dioxane and treated at 0° C. with bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at 0° C. for one hour. After addition of diethyl ether, the resulting crystals are filtered off with suction. The desired product is obtained in 81% yield (5.52 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([NH:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1)[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:40][CH2:41][N:42]([C:4](=[O:6])[CH:3]([NH:7][C:8]3[O:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:12]=3)[CH:2]([CH3:1])[CH3:19])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(Nc1nnc(-c2ccccc2)o1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
3-Methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoic acid (80 mg, 0.3 mmol), EDCI (65 mg, 0.33 mmol), 4-(4-chlorophenyl)-piperidine hydrochloride (78 mg, 0.33 mmol) and HOBt (40 mg, 0.3 mmol) were combined and suspended in DMF (2 mL). Diisopropylethylamine (210 μL, 1.2 mmol) was added and the reaction was stirred at rt. overnight. After this time, methanol (2 mL) was added to the reaction and the mixture was purified directly by preparative HPLC to give 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butan-1-one (60 mg, 30%). MS found: 439 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][NH2:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15](=S)=[S:16].C(N(CC)CC)C.[Cl-].[NH4+].[Cl-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:12][C:15]([SH:16])=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccc2ncccc2c1
Reactant: S=C=S
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Sc1nnc(-c2ccc3ncccc3c2)o1
Yield: 50.5 %

Procedure:
A solution of quinoline-6-carbohydrazide (2.00 g, 10.7 mmol), carbon disulfide (1.61 mL, 26.8 mmol) and triethylamine (1.78 mL, 12.8 mmol) in ethanol (40 mL) was heated under reflux for 4 hr. After cooling, the reaction mixture was poured into water, a saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was saturated with sodium chloride. The precipitate was collected by filtration and recrystallized from methanol to give the title compound (1.24 g, yield 51%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[CH2:13](N)[CH2:14][NH2:15]>>[CH3:1][CH:2]([CH3:12])[CH:3]([C:4]1[NH:5][CH2:13][CH2:14][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: CC(C)C(C#N)c1ccccc1
Product: CC(C)C(C1=NCCN1)c1ccccc1

Procedure:
rac-2-(2-Methyl-1-phenyl-propyl)-4,5-dihydro-1H-imidazole was prepared from rac-3-methyl-2-phenyl-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 203.0 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:28][NH2:29])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:30]2[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:42]([O:44][C:45](=[O:51])[CH:46]([CH:49]=O)[CH:47]=O)[CH3:43]>C(O)C>[CH2:42]([O:44][C:45]([C:46]1[CH:47]=[N:29][N:28]([C:26]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@@H:30]3[CH2:34][C@H:33]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:32]([OH:40])[C@H:31]3[OH:41])=[C:19]([NH:18][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:27]=2)[CH:49]=1)=[O:51])[CH3:43]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
To a solution of N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-hydrazino-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (0.1 g, 0.177 mmol) in dry ethyl alcohol (5 ml) is added 2-formyl-3-oxo-propionic acid ethyl ester (synthesised from ethyl-3,3-diethoxy-propionoate, as described in: Bertz S. H., Dabbagh G. and Cotte P.; J. Org. Chem. (1982) 47, pp 2216-2217) (0.033 g, 0.231 mmol). The reaction mixture is heated at reflux for 8 hours then concentrated in vacuo. The crude residue is purified by chromatography on silica (60-120 mesh) eluting with 3% methanol in chloroform to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 671).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].Cl>O>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 3.00 g (16 mmol) of 6-hydroxy-2-naphthoic acid, 40 mmol of sodium hydroxide, and 16 g of water, 1.59 g (18 mmol) of acryloyl chloride was added at 20° C., and the reaction was performed for 3 hours. After the reaction, the mixture was acidified by adding 4-mol/l hydrochloric acid dropwise and chilled with ice-water. The resultant precipitate was collected by filtration, dried in an oven at 40° C., and recrystallized from methanol-THF (2:3) mixed solvent to yield the desired product, 6-acryloyloxy-2-naphthoic acid, as while solid (2.07 g, Yield: 53.6%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:15]1[C:16]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:17]=2[C:18](=[O:21])[NH:19][CH:20]=1.[CH3:40][C:41](C)([O-])C.[K+].ICC>O1CCCC1>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:15]1[C:16]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:17]=2[C:18](=[O:21])[N:19]([CH2:40][CH3:41])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(ncn5C)c4Oc4ccc(F)cc4F)c[nH]c(=O)c32)cc1
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1cc(-c2ccc3c(ncn3C)c2Oc2ccc(F)cc2F)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A suspension of 4-[4-(2,4-difluorophenoxy)-1-methyl-1H-benzimidazol-5-yl]-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (33.2 mg, 0.0607 mmol) in tetrahydrofuran (1.0 mL) at 0° C. was treated with 1.0 M solution of potassium tert-butoxide in THF (0.0850 mL, 0.0850 mmol) and the resultant reaction mixture was stirred at 0° C. for 30 min, after which time the reaction mixture was treated with iodoethane (0.00680 mL, 0.0850 mmol), warmed to RT and stirred at RT for 19 h. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (15.4 mg, 44%). LCMS calculated for C30H25F2N4O4S (M+H)+: m/z=575.2. found: 575.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][OH:19])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C=CCC(CO)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of methanesulphonyl chloride (2.3 g) in dichloromethane (10 ml) was added to an ice-cooled solution of 4-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (4.3 g) (see Preparation 22) and triethylamine (2.5 g) in dichloromethane (50 ml) over 10 minutes. The mixture was stirred for a further 30 minutes before being washed sequentially with water (3×25 ml) and brine (25 ml), then dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 4-(3,4-dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])=[CH:4][C:5]2[N:10]=[N:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:12]=1.CC1[C:28]2[N:29]=[C:30](NC3SC=C(C(OCC)=O)N=3)N=N[C:27]=2[CH:26]=[C:25](C2C(C)=CC=CC=2C)C=1.BrC1SC=C(C(OCC)=O)N=1.Cl[C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1B(O)O>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=1[C:3]1[C:2]([Cl:1])=[CH:12][C:6]2[N:7]=[C:8]([NH:11][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:30][N:29]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:66][CH:65]=3)[N:9]=[N:10][C:5]=2[CH:4]=1.[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])=[CH:4][C:5]2[N:10]=[N:9][C:8]([NH:11][C:64]3[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:30][N:29]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:66][CH:65]=3)=[N:7][C:6]=2[CH:12]=1
Reactant: COc1ccc(Cl)c(-c2cc3nnc(N)nc3cc2Cl)c1
Reactant: CCOC(=O)c1csc(Nc2nnc3cc(-c4c(C)cccc4C)cc(C)c3n2)n1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Agent: CCOC(=O)c1csc(Br)n1
Product: COc1ccc(Cl)c(-c2cc3nnc(Nc4ccc(OCCN5CCCC5)cc4)nc3cc2Cl)c1
Product: Oc1ccc(Cl)c(-c2cc3nnc(Nc4ccc(OCCN5CCCC5)cc4)nc3cc2Cl)c1
Yield: 27 %

Procedure:
6-chloro-7-(2-chloro-5-methoxy-phenyl)benzo[1,2,4]triazin-3-ylamine designated on the reaction scheme (CCLXXVI) as compound 19 (54 mg, 68%) was prepared from compound 18 and 2-chloro-5-methoxyphenylboronic acid according to the above-described coupling procedure. The crude product was purified by silica gel column chromatography (Rf=0.41, EtOAc/hexanes 50:50). The title compound (CCLXXV) was prepared from compound 19 and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine following the above-described coupling procedure, followed by demethylation. The coupling product was purified by reverse phase preparative HPLC to give [6-chloro-7-(2-chloro-5-methoxy-phenyl)-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (28.7 mg, 27%). Deprotection of the methoxy group with BBr3 (22 μl, 0.23 mmol) in 2 mL CH2Cl2 at room temperature yielded 4-chloro-3-{6-chloro-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol, which was purified by reverse phase preparative HPLC and converted to the free amine to give a brown solid (13 mg, 57%). 1H NMR DMSO-d6: δ 1.68 (m, 4H), 2.50-2.55 (m, 4H), 2.79 (t, J=5.9 Hz, 2H), 4.07 (t, J=5.9, 2H), 7.07 (d, J=9.0 Hz, 1H), 6.77 (d, J=2.8, 1H), 6.84 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 7.32 (d, J=8.8, 1H), 7.85 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 8.22 (s, 1H), 10.90 (br s, 1H). MS (ESI+) m/z=496.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.CC1C(C)=NC=CC=1.[C:22](O)(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][O:12][C:22](=[O:24])[CH3:23])[CH2:3]1
Reactant: CC(=O)O
Reactant: CC1(C)CC(CO)c2ccccc21
Agent: Cc1cccnc1C
Solvent: Cc1ccccc1
Product: CC(=O)OCC1CC(C)(C)c2ccccc21
Temperature: 30 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
To a mixture of 12.3 g (70 mmol) of 1,1-dimethyl-3hydroxymethylindane (IX), 12.8 g of dimethylpyridine, and 20 ml of toluene, 8.6 g (84 mmol) of acetic acid was added dropwise over 10 minutes at room temperature. After the addition, the mixture was stirred for 5 hours at 30° C. to complete the reaction. After extraction with ether and removal of dimethylpyridine with 10% sulfuric acid, the residue was dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer and the residue was distilled under reduced pressure to produce 11.6 g (53 mmol) of (1,1-dimethylindane-3-yl)methylacetate at a yield of 76%. The product was a colorless, transparent liquid having a woody, floral odor with a weak fruity sensation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH2:19]([S:21][C:22]1([CH2:33][CH2:34]O)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[NH:24][C:23]1=[O:32])[CH3:20]>>[CH2:19]([S:21][C:22]1([CH2:33][CH2:34][N:16]2[CH2:15][CH2:14][N:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)[CH2:18][CH2:17]2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[NH:24][C:23]1=[O:32])[CH3:20]
Reactant: CCSC1(CCO)C(=O)Nc2ccc(F)cc21
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Product: CCSC1(CCN2CCN(C3CCCc4ccc(OC)cc43)CC2)C(=O)Nc2ccc(F)cc21
Temperature: 110 °C

Procedure:
A mixture of 8.1 g (0.0328 mole) of 1-(7-methoxy-1,2,3,4-tetrahydro-1-naphthyl)piperazine and 6.7 g (0.0164 mole) of 3-(ethylthio)-5-fluoro-3-(2-hydroxyethyl)-1,3-dihydro-2(2H)-indolone is heated to 110° C. for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:17])([OH:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) was added methylmagnesium bromide (21.4 ml of 1.4M solution, 29.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added aqueous saturated NH4Cl solution and EtOAc. The organic phase was washed with brine and dried with MgSO4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120 g silica gel column).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:43][C:33]1[CH:38]=[CH:37][C:36]([S:39]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 15.6 g (50.0 mmole) of [(2S)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol in 100 mL of methylene chloride was added 26.3 mL (0.15 mole) of N,N-diisopropylethylamine, 0.63 g (5 mmole) of 4-dimethylaminopyridine and 14.25 g (75.0 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. Combination of the product fractions and concentration in vacuum gave 18.0 g (77%) of the (R)-enantiomer of the title compound as a white solid, m.p. 76-77° C.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[C:5](=[O:16])[C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>CO>[OH:1][C:4]1[C:5](=[O:16])[C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
A solution of 10% aqueous potassium hydroxide (150 mL) was added to a solution of 2-chloro-3-methyl-1,4-naphthoquinone (10.3 g) in refluxing methanol (500 mL). After cooling and acidification with concentrated hydrochloric acid, the precipitated product was collected by filtration to give 2-hydroxy-3-methyl-1,4-naphthoquinone, m.p. 173°-174° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:36]3[CH2:40][CH2:39][O:38][N:37]=3)[CH2:23][C:24]([O:26]CC3C=CC(OC)=CC=3)=[O:25])=[CH:18][CH:17]=2)=CC=1>C(Cl)Cl>[O:38]1[CH2:39][CH2:40][C:36]([CH:22]([C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[CH2:23][C:24]([OH:26])=[O:25])=[N:37]1
Reactant: COc1ccc(COC(=O)CC(C2=NOCC2)c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(C1=NOCC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.1 %

Procedure:
TFA (1 mL) was added to 42.1 (100 mg) in DCM (1 mL). The mixture was stirred at room temperature for 40 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. The filtrate was concentrated to give 42.2 (50 mg), which was used in the next step without further purification. MS ESI (pos.) m/e: 236 (M+H).