Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.Cl.[C:7]1([CH3:15])[CH:12]=[CH:11][C:10]([NH:13]N)=[CH:9][CH:8]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH3:15])=[CH:12][C:11]=3[C:19]=2[CH2:18]1
Reactant: CN1CCCCC1=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Sulfuric acid (2 mL) was added to a solution of p-tolyl hydrazine hydrochloride (6.0 g, 37 mmol) in dioxane (60 mL), and stirred for 5 min. at RT. N-Methyl piperidone (5.03 g, 41 mmol) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture was extracted with EtOAc (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to provide the desired compound as a brown colored solid (4.0 g, 52% yield). 1H NMR (DMSO-d6, di-HCl salt) δ (ppm): 7.30 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.80 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:29]1[S:23][C:24](=[S:25])[N:26]([CH2:15][C:16]([OH:18])=[O:17])[C:27]1=[O:28])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:22])[S:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C1CSC(=S)N1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 1.25 g of rhodanine, 1 g of ammonium chloride 1 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: CN(C)CCCN=C=NCC.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][C@@H:24]([F:27])[C@@H:23]3[C@H:19]2[CH2:20][NH:21][CH2:22]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:70]CCl>>[ClH:70].[CH3:50][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:21]1[CH2:20][C@@H:19]2[C@@H:23]([C@H:24]([F:27])[CH2:25][CH2:26][C:18]2([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:22]1)=[O:48]
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Reactant: ClCCl
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Product: Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 50 cm3 of dry dichloromethane is added over 10 minutes to a solution, cooled to +4° C., of 0.72 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole, 0.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid, 0.03 g of 1-hydroxybenzotriazole in 75 cm3 of dichloromethane, followed by 0.37 cm3 of diisopropylethylamine. The reaction mixture is stirred for 3 hours at 0° C. and then washed twice with 50 cm3 of water and twice with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 21 cm3 of 0.1N hydrochloric acid, 50 cm3 of diethyl ether and 30 cm3 of water. The aqueous phase is separated and freeze-dried to give 0.85 g of (3aR,7R,7aR)-2-{[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, in the form of a white freeze-dried product.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25](O)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:3])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(CC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of oxalyl chloride (1.25 g, 0.17 mL, 2.6 mmol) in dichloromethane (5 mL) was cooled to -78°60 C. in a flame dried flask under a nitrogen atmosphere with stirring. A solution of dimethylsulfoxide (0.41 g, 0.37 mL, 5.2 mmol) in dichloromethane (5 mL) was added dropwise; then the reaction mixture was stirred for 15 minutes. A solution of 1-benzyl-4-(2'-(4''-fluorophenyl)hydroxyethyl)piperidine (0.6 g, 2 mmol) in dichloromethane was added dropwise, then the reaction mixture was stirred at -65° to -60° C. for 15 minutes. The mixture was then cooled to -78° C. and triethylamine (0.73 g, 1.0 mL, 7.2 mmol) was added in one portion. The reaction mixture was stirred while being warmed gradually to ambient temperature. After 3 hours, the reaction mixture was poured onto water (100 mL), mixed and extracted three times with ether. The combined organic layers were dried over magnesium sulfate filtered and concentrated in vacuo. Column chromatography (ethyl acetate) gave an oil (588 mg, Rf=0.2):1H-NMR:7.4-6.9(m,9H), 4.65(s,2H), 4.5(s,2H), 3.0-2.9(m,2H), 2.5-2.35(m,1H), 2.1-1.6(m,8H); HR-MS:Calcd for C20H22FNO:311.1700; Found:311.1693.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[CH:21]1([C:24]#[C:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:26]([OH:31])([C:25]#[C:24][CH:21]2[CH2:22][CH2:23]2)[C:27]([F:28])([F:29])[F:30])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(C#CC1CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (−50° C.) solution of 643 mg(2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.9 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at −50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO3, then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg(56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH3—CI): 391((M+H)+, 100%); 291((M+H-t-Boc)+, 49%). 1H NMR(300 MHz, CDCl3) δ 9.08(br. s, 1H); 8.29(br. s, 1H); 7.59(s, 1H); 1.50(s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).
Reaction SMILES: [C:1]([CH2:5][C@H:6]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[OH2:20].CN1[CH2:27][CH2:26][O:25][CH2:24]C1>C1COCC1>[CH2:26]([O:25][C:24]([NH:7][C@@H:6]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[CH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[C:27]1[CH:8]=[CH:6][CH:5]=[CH:1][CH:2]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)C[C@@H](N)C(=O)N[C@@H](CC(C)(C)C)C(=O)O
Reactant: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
3-tert-Butyl-D-alanyl-3-tert-butyl-L-alanine (3.73 g, 12.1 mmol, example 92A) is dissolved in THF (170 ml) under an argon protective gas atmosphere. After the addition of water (170 ml), benzyloxycarbonyloxysuccinimide ester (4.52 g, 18.1 mmol, 1.5 equivalents) and N-methylmorpholine (4.28 g, 4.23 mmol, 3.5 equivalents) at 0° C., the mixture is stirred vigorously at RT until all starting material has been converted (several hours, HPLC monitoring, Method 2). The mixture is quenched with glacial acetic acid. The THF is drawn off in vacuo. The remaining aqueous phase is layered with ethyl acetate, adjusted to pH<3 with 4 N hydrochloric acid and then extracted several times with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting foam is stirred with acetonitrile, whereby a solid forms which is collected by filtration, then washed with a little acetonitrile. This process can be repeated several times more with the filtrate once it has been concentrated. The combined solids are dried under high vacuum whereby the title compound is obtained as a solid. The remaining mother liquor is concentrated and purified by means of preparative HPLC (Method 10). The title compound (combined solids and purification product from HPLC separation) is obtained as a solid (3.49 g, 71% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(O)C.O>N1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Yield: 62.4 %

Procedure:
Treatment of 4-(4-aminophenoxy)-1-(4-pyridyl)piperidine (see Preparation 3) (0.323 g) with methanesulphonyl chloride (0.151 g) in pyridine (10 ml) according to the method of Example 1 gave the title compound, (0.260 g), m.p. 191°-192° (from ethanol/water).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](=[O:21])[NH2:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[NH2:20]
Reactant: COc1ccc2c(C(N)=O)cn(CC(=O)OC(C)(C)C)c2c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C(N)=O)cn(CC(=O)O)c2c1
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-6-methoxy-indol-1-yl)-acetic acid tert-butyl ester (300 mg, 0.99 mmol) in CH2Cl2 (9 mL) was added TFA (4.5 mL) at RT, and stirring was continued for 2 h. Methanol was then added to the reaction mixture, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated under reduced pressure to afford the title compound as a grey solid: MS: 249 [M+H]+, 497 [2M+H]+; tR (HPLC conditions c): 2.86 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[S:13]1C=CC=C1CC(O)=O.C(O)(=O)C>CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:12])=[S:13])=[CH:2]1
Reactant: O=C(O)Cc1cccs1
Reactant: N#CCc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=S)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of (1H-indol-3-yl)-acetonitrile (5.0 g, 32 mmol), thiolacetic acid (6.8 mL, 96 mmol) and glacial acetic acid (25 mL) was heated at 100° C. for 4 h. After cooling to room temperature the reaction mixture was diluted with EtOAc, washed with water twice and brine. The organics were then concentrated under vacuum and purified by column chromatography (SiO2, EtOAc/hexanes) to afford 2-(1H-indol-3-yl)-thioacetamide as an orange solid (2.9 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[Si]([C:15]#[N:16])(C)(C)C.B.C1COCC1.CO>C1COCC1.[Zn+2].[I-].[I-]>[NH2:16][CH2:15][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: B
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: C1CCOC1
Product: NCC(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 772 %

Procedure:
To a mixture of 3,4-dichlorobenzaldehyde (3.50 g, 20.2 mmol) and ZnI2 (19 mg, 0.06 mmol) at 0° C. was added TMSCN (2.2 g, 2.2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then warmed to rt and stirred for an additional 1 h. The mixture was concentrated to afford an orange-brown colored oil. The oil was dissolved in THF (20 mL) and BH3.THF (1 M in THF; 25 mL, 25 mmol) was added at 0° C. The reaction mixture was warmed to rt and stirred overnight. The mixture was cooled to 0° C. and MeOH (6 mL) was added with continued stirring for 2 h. After being warmed to rt, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and HCl (2 M in Et2O; 25 mL) was added at 0° C. After 30 min, Et2O (100 mL) was added and the resulting white solid was filtered and washed with Et2O (2×50 mL) to give a white solid (3.5 g, 72%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:16])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together morpholine (0.174 mL, 2.0 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (260 mg, 66%) as a white solid. MS ISP (m/e): 372.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.25 (d, 2H), 8.04 (s, 1H), 7.80 d, 2H), 3.83 (br s, 4H), 3.74 (m, 4H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH3:12][N:13]=[C:14]=[O:15].C[NH:17][C:18]([N:20]1C2C(=CC=CC=2)C(=O)C1=O)=[O:19].Br.C(SC(=N)N)C>O1CCCC1.C(N(CC)CC)C>[CH3:12][N:13]1[C:4]2([C:2](=[O:3])[NH:20][C:18](=[O:19])[NH:17]2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:14]1=[O:15]
Reactant: CN=C=O
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CNC(=O)N1C(=O)C(=O)c2ccccc21
Agent: Br
Agent: CCSC(=N)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)Nc2ccccc2C12NC(=O)NC2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Isatin (294.3 g) is suspended in tetrahydrofuran (3 liter) and thereto are added with stirring triethylamine (279 ml) and methyl isocyanate (129.8 ml) at 15° C. The mixture is stirred at 20°-25° C. for 2.5 hours (1-methylcarbamoylisatin is produced in the mixture). To the reaction mixture are added 2-ethylisothiourea hydrobromide (444.2 g) and triethylamine (55.8 ml), and the mixture is refluxed for 2 hours. After cooling, the solvent is distilled off under reduced pressure. To the residue [i.e. 3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (4 liter) and the mixture is stirred at 70° C. for 4 hours. After cooling, the precipitates are taken by filtration, washed with water, methanol (1 liter) and chloroform (1 liter) in this order and then dried to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (369.2 g, yield 75 %).
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)C(=O)OC(C)(C)C)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:45]([Cl:51])(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47]>O>[ClH:51].[CH3:47][C:46]([CH3:49])([CH3:48])[C:45]([N:29]1[CH2:30][CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:27]([CH2:26][NH:18][C@@H:16]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH3:17])[CH2:28]1)=[O:50]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](NCC1CN(C(=O)C(C)(C)C)CC1c1ccccc1)c1cccc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 6 ml THF solution of 300 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 0.29 ml of triethylamine and 0.13 ml of pivaloyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, 20 ml of water was added thereto and THF was evaporated. This was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate, and then the organic layer was concentrated. The thus obtained residue was mixed with 10 ml of 4 M hydrogen chloride/ethyl acetate and stirred at 50° C. for 4 hours. After completion of the reaction, the solvent was evaporated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and crystallized (diethyl ether-ethyl acetate) to obtain 92 mg of (1R)—N-{[1-(2,2-dimethylpropanoyl)-4-phenylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine hydrochloride as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH2:23]([NH2:25])[CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C@H:10]([C:12]([NH:25][CH2:23][CH3:24])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: CCN
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and ethylamine: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8, 2.7 Hz, 1H), 6.33 (bs, 1H), 4.27 (q, J=7.2 Hz, 1H), 3.40-3.20 (m, 4H), 1.51 (d, J=7.1 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H), 1.04 (m, 1H), 0.68 (m, 2H), 0.34 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[N:22]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:20]=[C:19]([O:33][C@H:34]([CH3:40])[C:35](OCC)=[O:36])[CH:18]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[CH:18]=[C:19]([O:33][C@H:34]([CH3:40])[CH2:35][OH:36])[N:20]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:22]=2)(=[O:14])=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (2R)-2-({6-[({5-[(tert-butylamino)carbonyl]-2-furyl}sulfonyl)amino]-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl)oxy)propanoate (the product of step iii) (0.25 g) in THF (10 mL) was added a solution of lithium borohydride (0.6 mL, 2.0M in hexanes) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 18 h. After cooling to 0° C., 1N HCl (20 mL) was added slowly, and the mixture extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude oil was purified by reverse phase HPLC (75% to 5% gradient of 0.2% aqueous trifluoroacetic acid in acetonitrile as eluent) to give the title compound as a white solid. Yield: 90 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.20 g, 0.73 mmol) in CH2Cl2 (5 mL) was added dropwise a solution of tert-butyl piperidin-4-ylcarbamate (0.19 g, 0.95 mmol) and triethylamine (203 μL, 147 mg, 1.46 mmol) in CH2Cl2. The reaction was stirred for 3 h and then quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain tert-butyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate. The residue was dissolved in 10 mL CH2Cl2 and 3 mL TFA. The reaction was stirred for 2 hours and neutralized with a 1.0 M aqueous NaOH solution. The mixture was partitioned between H2O/CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain 2-(4-(4-aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z 339.3 (M+H)+ at 1.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4](S)[N:3]=1.CO>O.C(Cl)Cl.[Ni]>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)[CH3:9]
Reactant: CCc1cc(O)nc(S)n1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCc1cc(=O)[nH]cn1
Yield: 97.2 %

Procedure:
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethyl pyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL). The suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10% MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid (70.0 g; 98%). The product is used without further purification for the next step.