Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:31](=[O:32])[C:30]2[CH:29]=[C:28]([C:27]([F:42])([F:41])[F:26])[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (47 mg, 0.22 mmol) and DIPEA (57 μL, 0.33 mmol) was added 3,5-bis(trifluoromethyl)benzoyl chloride (78 mg, 0.28 mmol, CAS RN 1271-19-8) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound as a waxy oil which solidified upon standing (56 mg, 56%). MS (ESI): m/z=457.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:39])=[O:29])=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 0.50 mmol) and K2CO3 in DMF (2 mL) was added CH3I (0.2 g, 1 mmol). The resulting mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give the crude product, which was purification by TLC to afford methyl 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetate (100 mg, 37%). 1H NMR (CDCl3): δ=1.42 (d, 3H), 1.68 (m, 1H), 1.88 (m, 2H), 2.12 (m, 1H), 2.23 (m, 2H), 2.78 (m, 1H), 3.29 (m, 2H), 3.44 (s, 2H), 3.64 (s, 3H), 3.75 (s, 3H), 4.28 (s, 2H), 5.56 (q, 1H), 6.73 (m, 4H), 6.92 (m, 2H), 7.14 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH2:22])[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][CH2:20][N:19]([CH2:23][CH3:24])[CH2:17][CH3:18])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-diethylaminoethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.C(OP(C#N)(=O)OCC)C>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][C:21](=[O:22])[CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.2 ml of triethylamine are added dropwise at 0° to a solution of 3.36 g (16 mmol) of (L)-valine-tert-butyl ester.HCl, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml of DMF. The reaction mixture is stirred for 48 h at RT, and then diluted with methylene chloride and washed with 10% citric acid as well as saturated sodium hydrogen carbonate solution. The organic phase is filtered through cotton wadding and, after removal of the solvent by evaporation, yields N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester, which is directly further used in a).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([OH:10])=O)[CH3:2].Cl.[CH:12]([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH:12]([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH:18][C:8](=[O:10])[C@@H:4]1[C@@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][NH:5]1)([CH3:14])[CH3:13]
Reactant: CC[C@H]1CCN[C@@H]1C(=O)O
Reactant: CSCC[C@H](N)C(=O)OC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H]1CCN[C@@H]1C(=O)N[C@@H](CCSC)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]3(S)-ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydrochloride (2.21 g, 0.0097 mol), HOBT (1.49 g, 0.0097 mol) and EDC (1.86 g, 0.0097 mol) were dissolved in DMF (15 mL) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol). The reaction mixture was stirred overnight at room temperature, then concentrated and partitioned between EtOAc and H2O. The organic layer was washed with aq satd NaHCO3 solution, brine, and dried (MgSO4). The crude product was chromatographed on a flash silica gel column eluting with hexane: EtOAc, 7:3 to give N-(t butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]3(S)-ethyl-prolyl-methionine isopropyl ester.
Reaction SMILES: [CH2:1]([CH2:6][O:7][CH2:8][CH2:9][NH2:10])[O:2][CH2:3][CH2:4][NH2:5].[CH3:11][CH:12]([CH3:17])[CH2:13][C:14](=O)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH2:6]([O:7][CH2:8][CH2:9][NH:10][CH:14]([CH2:13][CH:12]([CH3:17])[CH3:11])[CH3:15])[CH2:1][O:2][CH2:3][CH2:4][NH:5][CH:14]([CH2:13][CH:12]([CH3:17])[CH3:11])[CH3:15]
Reactant: NCCOCCOCCN
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(C)NCCOCCOCCNC(C)CC(C)C
Temperature: 23 °C

Procedure:
A 1 liter 3 necked round bottomed flask fitted with condenser, mechanical stirrer, dropping funnel, thermocouple and nitrogen inlet at <20 mL/min was charged with 20 g (0.1350 mol) of 2,2′-(ethylenedioxy)bis(ethylamine) in 450 mL of dichloromethane. STAB (31.44 g) was added with stirring. 31.0 g of 4-methyl-2-pentanone was then added drop-wise to the suspension over 40 mins. After cooling to 23° C. with an ice bath the mixture was stirred at room temperature for about 1.5 hours and left standing for a further day. The crude product was stirred with a mixture of saturated aqueous sodium carbonate solution (30%) (120 ml) and water (60 ml). The aqueous phase was diluted with water (100 ml), shaken, separated and washed with DCM (50 ml). The combined organic phase was washed with water (2×150 ml). It was then dried by shaking with magnesium sulphate and filtered.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26](C3CCCCO3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[NH2:35][CH2:36][CH2:37][NH:38][C:39](OC(C)(C)C)=O.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.FC(F)(F)C(O)=O>>[CH3:39][N:38]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([C:12]([C:13]3[S:14][C:15]([C:24]4[NH:28][CH:27]=[N:26][N:25]=4)=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)=[C:2]([CH3:1])[N:3]=2)[CH:6]=1)[CH2:37][CH2:36][NH2:35]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(CN(C)CCN)cn2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.1 %

Procedure:
The mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol) and N-(2-aminoethyl)(tert-butoxy)carboxamide (15.3 mg, 0.0956 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) and Acetic acid (50 mg, 0.8 mmol) was stirred at r.t. for 20 min. Sodium triacetoxyborohydride (23.3 mg, 0.110 mmol) was added and the mixture was stirred at r.t. for 21 hours. Paraformaldehyde (25 mg, 0.28 mmol) was added, followed by Acetic acid (100 mg, 2 mmol). The mixture was stirred at r.t. for 10 min. Sodium triacetoxyborohydride (172 mg, 0.812 mmol) was added and the mixture was stirred at r.t. for 17 hours. The mixture was quenched with saturated NaHCO3, extracted with DCM. The DCM solution was washed with water, brine, dried over Na2SO4, filtered. The filtrate was chromatographed in a 24 g ISCO column using MeOH/DCM (0/100 to 5/95) to give a solid. LCMS: (FA) ES+ 629. This solid was treated with Trifluoroacetic Acid (1.0 mL, 13 mmol) in Methylene chloride (1.0 mL, 16 mmol) at r.t. for 18 hours. The mixture was rotavaped, azeotroped with DCM. The residue was triturated with Et2O and decanted to give a solid residue, dried in hi-vac to give 30 mg of crude product. HPLC purification gave a solid product (0.0040 g, 13.8% yield). LCMS: (FA) ES+ 445, ES− 443. 1H NMR (400 MHz, d4-methanol) δ 9.88 (s, 1H), 8.47 (s, 1H), 7.78-7.81 (m, 2H), 7.61 (s, 2H), 7.41-7.43 (m, 3H), 3.68 (s, 2H), 3.00-3.03 (m, 2H), 2.75 (s, 3H), 2.66-2.69 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:22].[C:23]1([C:29]2[NH:30][C:31]([CH3:37])=[C:32]([CH:34]([Cl:36])[CH3:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:30][C:31]=3[CH3:37])[CH3:35])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1C(C)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 55 %

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol:water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4-[1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl]piperazine trihydrochloride (55% yield), which melted at 215° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1>C(OCC)(=O)C.[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Rh+3].[Cl-].[Cl-]>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]2=[O:21])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1C=Cc1ccc(CCO)cc1
Agent: [Rh+3]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Reaction time: 24 h
Yield: 85 %

Procedure:
2-{2-[4-(2-hydroxy-ethyl)phenyl]-vinyl}-isoindole-1,3-dione (Preparation 9, 62.0 g, 211.37 mmol) was dissolved in ethyl acetate (1200 mL). To this was added rhodium tris(triphenylphosphine)chloride, (12.7 g, 13.7 mmol) and the mixture hydrogenated at 20 psi, room temperature for 24 hours. The reaction was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (1000 mL) and passed through a pad of silica gel, washing with ethyl acetate. The solvent was removed in vacuo to yield a light brown solid which was recrystallised from ethyl acetate:heptane (4:1, by volume) to yield the title compound as an off-white crystalline solid, in 85% yield, 53 g,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19]CS([O-])(=O)=O)[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([O:12][CH3:13])[CH2:9]1.[N-:26]=[N+:27]=[N-:28].[Na+].S([O-])(=O)(=O)C.CO.C(Cl)(Cl)Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:26]=[N+:27]=[N-:28])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([O:12][CH3:13])[CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1CN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC1CN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
(R)-[[3-[3-fluoro-4-(3-methoxy-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (0.508 g, 1.36 mmol) was combined with sodium azide (0.106 g, 1.63 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was heated to 65° C. under a nitrogen atmosphere. After 2 hours, a small amount of the starting mesylate still remained by TLC analysis (5% methanol/chloroform). An additional 0.044 g of sodium azide was added and the reaction heated for a further 1.5 h, at which time TLC revealed the reaction to be complete. The reaction mixture was filtered and concentrated in vacuo. The residue was chromatographed over silica gel (25 g), eluting with a gradient of 1-3% methanol/chloroform. Appropriate fractions were combined and concentrated in vacuo to furnish 0.426 g (98%) of the title compound as an off-white solid. An analytical sample was prepared by recrystallization of this material from 3:1 ethyl acetate/hexane to give a white solid with mp 111°-112.5° C. and MS(EI) 321 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH2:16]1[CH2:17][O:18][C:2]2([CH2:7][CH2:6][CH2:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:8]#[N:9])[CH2:3]2)[O:1]1
Reactant: N#CC1(c2ccccc2)CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: N#CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 111 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
The mixture of 3-oxo-1-phenylcyclohexanecarbonitrile (2.62 g), ethylene glycol (3.65 mL) and pyridinium p-toluene sulfonate (1 spatula) in benzene (40 mL) was stirred at 111° C. with Dean-Stark apparatus overnight. After cooling down to room temperature, the mixture was washed with saturated sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by Flash Chromatography with from 25% ethyl acetate/75% hexane to 30% ethyl acetate/70% hexane over 20 minutes. The title compound was obtained as a white solid (1.66 g, 48% yield in 2 steps). 1H NMR (400 MHz, CDCl3) δ 1.56 (1H, dt, J=4, 16 Hz), 1.70–1.79 (1H, m), 1.89–1.96 (3H, m), 2.06–2.28 (3H, m), 3.89–3.97 (2H, m), 4.03–4.12 (2H, m), 7.28–7.32 (1H, m), 7.36–7.39 (2H, m), 7.48–7.51 (2H, m). HPLC purity (retention time): 95% (1.62 min, method C). MS: 266.37 (M+Na+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CS(C)=O.[Cu]I>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]3[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]3=[O:19])[CH:7]=2)=[CH:25][CH:24]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCc1ccc(Oc2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
A mixture of 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (200 mg, 0.57 mmol), 4-chlorophenol (110 mg, 0.86 mmol), copper(I) iodide (109 mg, 0.57 mmol), 1,10-phenanthroline (103 mg, 0.57 mmol) and potassium phosphate (483 mg, 2.28 mmol), in dimethylsulfoxide (3.5 ml) is heated to 200° C. under microwave irradiation for 30 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid and extracted with dichloromethane. The organic extract is washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-[5-(4-chlorophenoxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][CH:6]=[N:7]2.S(Cl)([Cl:17])=O.CN(C)C=O>>[Cl:17][C:4]1[C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[F:1])[N:7]=[CH:6][N:5]=1
Reactant: COc1cc(F)c2c(O)ncnc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(F)c2c(Cl)ncnc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a suspension of 5-fluoro-7-methoxyquinazolin-4-ol (0.125 g, 0.644 mmol) in thionyl chloride (1.410 mL, 19.31 mmol) was added N,N-dimethylformamide (0.028 mL, 0.361 mmol). The reaction was stirred at 80° C. for 6 hours and concentrated in vacuo. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was concentrated in vacuo to generate the title compound (0.13 g, 0.611 mmol) as a yellow solid. LC/MS (ESI+) m/z=213 (M+H).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S-:23][C:24]#[N:25].[K+].BrBr>O>[NH2:25][C:24]1[S:23][C:21]2[CH:22]=[C:16]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: N#C[S-]
Reactant: CCCCCCCCCCOc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCOc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Next, acetic acid (100 ml) was added to the 4-decyloxyaniline 3 (23.4 g, 93.7 mmol) thus obtained, and potassium thiocyanate (23.5 g, 242 mmol) was then added thereto. The solution was thoroughly cooled in an ice bath, and an acetic acid solution of bromine (5.8 ml/50 ml) was then added dropwise thereto over a period of about 3 hr. After the completion of the dropwise addition of the solution, the mixture was stirred at room temperature for about 2 hr. Thereafter, water (200 ml) was added, and the mixture was refluxed for about 30 min and was then hot-filtered. The filtrate was made alkaline by the addition of aqueous ammonia, and saturated brine was further added thereto. The precipitated solid was collected by filtration to give 2-amino-6-decyloxybenzothiazole 4 (14.22 g, 49.5%) as a light purple solid. The product was purified by column chromatography on silica gel (hexane: AcOEt=1:2).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([NH:36][CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([NH:36][CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(NC(=NC#N)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-n-propyl-4-methyl-6-(2-cyano-3-methyl-guanidino)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[C:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1>CCO>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc2c(c1)C(c1ccccc1)NCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.65 g (17.1 mmol) of NaBH4 were added in portions to a solution of 3.2 g (max. 14.2 mmol) of the crude product 7-fluoro-1-phenyl-3,4-dihydroisoquinoline in EtOH (80 ml) and the mixture was then stirred for 16 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with DCM (200 ml). It was washed with water and the aqueous phase was extracted with DCM (2×150 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroisoquinoline was obtained as the crude product, which was reacted further with no additional purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.4 (br, 1H), 8.75 (s, 1H), 7.79 (m, 1H), 7.62 (d, 1H), 7.27-7.46 (m, 5H), 6.36 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.90 (s and t, 5H), 3.49 (s, 3H); LC-MS (ESI) m/z 549 (M+H)+.