Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 9.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(=S)=S>[C:5]1([CH3:11])[CH:10]=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(C)cc1
Yield: 67275272 %

Procedure:
Anhydrous aluminum chloride (89.6 g, 0.67 mol) was added to a solution of toluene (28.5 g, 0.3 μmol) in 120 mL of dry carbon disulfide. The mixture was heated to reflux and acetic anhydride (24.5 g, 0.24 mol) was added over one hour. Heating was continued for an additional hour. The solvent was removed by distillation. The reaction mixture was cooled and slowly poured into a well-stirred mixture of ice and hydrochloric acid. The mixture was extracted several times with ether. The combined extracts were washed with water and 10% sodium hydroxide, dried over calcium chloride, filtered, and the solvent was removed. Distillation gave the desired product 1-p-tolyl-ethanone (27.08 g). 1H NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 2.50 (s, 3H), 7.32 (d, 2H), 7.85 (d, 2H); EI-MS (M+): 134.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Br)=[CH:46][CH:45]=1>CC#N>[Br:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]3)(=[O:14])=[O:13])=[CH:46][CH:45]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-4-(bromomethyl)benzene (602 mg, 2.409 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (632 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.59-7.55 (m, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.84 (d, J=9.1 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 2H), 2.79 (t, J=6.7 Hz, 2H), 1.83 (t, J=6.7 Hz, 2H), 1.35 (s, 6H), 1.33 (s, 9H). LRMS [ESI, MH+] m/z calcd for C24H31BrNO5S 524.11, found 524.1.
Reaction SMILES: C([O:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([S:17][C:18](=[O:20])[CH3:19])[CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])(=O)C.O>CC(O)C>[C:18]([S:17][CH:10]([CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:21])=[O:4])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(=O)CCCCC(CCSC(C)=O)SC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(=O)SCCC(CCCCC(=O)O)SC(C)=O
Reaction time: 4.25 h

Procedure:
The anhydride from step 2 (8.0 g) was mixed with 30 mL of water and 30 mL of 2-propanol and stirred at 40 for 4.25 hr. After about 2 hr there was a clear solution. The solvent was evaporated under vacuum (2 mm) at 25. The oil remaining was evaporated with 10 mL of water to remove any residual 2-propanol and acetic acid. An almost colorless oil weighing 6.8 g was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8]OS1(=O)=O.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[Li]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][CH2:9][CH2:8][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: [Li]c1cccs1
Reactant: O=S1(=O)OCCN1Cc1ccccc1Cl
Product: Clc1ccccc1CNCCc1cccs1

Procedure:
contacting the N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine with thienyllithium to give N-(2-chlorobenzyl)-2-(2-thienyl)ethylamine, and
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[N:12]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=1
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: O=c1cc(I)c(F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (1.77 g, 5.44 mmol) was added to a suspension of 5-fluoro-4-iodopyridin-2(1H)-one (1.00 g, 4.2 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.56 g, 5.44 mmol) in anhydrous THF (45 mL). The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in n-heptane (30-80%) to afford the title compound as a yellow residue (691 mg, 37%). MS (LCMS) m/z 446.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, 3 H) 1.75 (s, 3 H) 2.37-2.57 (m, 2 H) 3.10 (s, 3 H) 3.83-4.02 (m, 1 H) 4.16-4.37 (m, 3 H) 7.15 (d, 1 H) 7.20 (d, J=3.32 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:20]C([N-]C(C)C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
3.25 g (13.53 mmol) of methyl 9H-xanthene-9-carboxylate are dissolved in 70 ml THF, the solution is cooled with an ice bath and 10.15 ml (20.29 mmol) of a 2M solution of LDA are added drop wise whilst keeping the temperature at 0° C. After stirring at room temperature for 1 hr, 1.68 ml (27.06 mmol) of iodomethane are added drop wise and the system is stirred at rt overnight. The solution is poured over excess of saturated solution of ammonium chloride and is extracted thrice with ethyl ether. After washing with brine, the solution is dried and concentrated to give a reddish residue which is purified by column chromatography (Cl3CH/hexane from 1:3 to 1:1) to give 2.6 g of the title compound (75% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[CH2:8][C@@H:7]1[CH2:6][O:5][C:4]2=[O:9].[H-].[Na+].[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>C1COCC1>[CH2:18]([O:1][CH2:2][C@@:3]12[CH2:8][C@@H:7]1[CH2:6][O:5][C:4]2=[O:9])[C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1OC[C@H]2C[C@@]12CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2C[C@@]12COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (1R,5S)-1-(hydroxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (3a, 100 mmol, prepared according to Moon, H. R., et al. Nucleosides, Nucleotides and Nucleic Acids, 2007, 26, 975-978) in THF (200 mL) at 0° C. was added NaH (60% in mineral oil, 4.80 g, 120 mmol). After 10 min, BnBr (120 mmol) was added. After stirring at room temperature for 12 h, the reaction was cooled to 0° C., and to the reaction was added saturate aqueous NH4Cl (50 mL) and water (50 mL). The mixture was extracted with ether (300 mL). The organic layer was washed with water (100 mL), brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by column (0-20 ethyl acetate in hanexane) to give a colorless liquid (3b). LCMS (ESI) m/z=219 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2].O1CCCC1.[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH2:12][Br:19])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.7 %

Procedure:
A 100ml flask was charged with 27.8 g of 5-acetylpyrazole-3-carboxylic acid ethyl ester and 40 ml of tetrahydrofuran. To this mixture, 56.4 g of phenyltrimethylammonium tribromide were added. The resulting red mixture was stirred at room temperature for 1 hour and poured into 600 ml of water. The resulting mixture was filtered and the solids were washed with more water. The solids were collected, air-dried and recrystallized from 1:1 mixture of disopropyl ether and hexanes (300ml) to afford 33.1 g of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester as white solids, mp 174°-176° C. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 4.57 (s, 2H), 7.4 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[I:12]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.OS([O-])=O.[Na+].[Na+].[Cl-]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([F:11])[C:3]=1[I:12]
Reactant: Fc1cc(F)c2c(c1)OCO2
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Fc1cc2c(c(F)c1I)OCO2
Reaction time: 20 h
Yield: 76 %

Procedure:
4,6-Difluorobenzo[d][1,3]dioxole (300 mg, 1.9 mmol) and N-iodosuccinimide (640 mg, 2.9 mmol) were combined in dry acetonitrile (5 mL), treated with trifluoroacetic acid (430 mg, 3.8 mmol) and stirred for 20 h. The mixture was stirred with a solution of NaHSO3 (100 mg in 2 mL water) and then shaken with ethyl acetate (30 mL) and saturated NaCl (5 mL). The organic phase was washed with saturated NaCl (5 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-5% ethyl acetate-hexane gradient to give the title compound as a white solid (410 mg, 76%): mp 65-66° C. 1H NMR (400 MHz, CDCl3) δ 6.54 (dd, J=6.9, 1.6 Hz, 1H), 6.07 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −99.31, −117.98; EIMS m/z 284.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH3:41])[C:34]([C:42]([O:44]C)=[O:43])=[CH:33][C:32]=5[C:31]4=[O:46])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH3:41])[C:34]([C:42]([OH:44])=[O:43])=[CH:33][C:32]=5[C:31]4=[O:46])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCOc1c(CN2CCC(N3CCc4nc(CC)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(CN2CCC(N3CCc4nc(CC)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
2M aqueous sodium hydroxide solution (20 mL) was added to a solution of methyl 6-(1-((6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (6.94 g) in methanol (20 mL) at room temperature. The mixture was stirred at 70° C. under nitrogen atmosphere for 2 hours. The mixture was neutralized with 1M hydrochloric acid at room temperature and stirred at 70° C. for 1 hour and at room temperature for 16 hours to give colorless crystals. After filtration, the crystals were dissolved in ethanol. The solution was filtrated and the filtrate was concentrated in vacuo to give a colorless solid. The solid was recrystallized from ethanol-DMSO-water (45 mL-5 mL-130 mL) to give the title compound (6.24 g).
Reaction SMILES: Cl.Cl[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[N:18][N:19]([CH3:22])[C:20]=3[CH3:21])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[C:20]([CH3:21])=[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[C:3]([C:30]4[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:28][CH:29]=4)=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11]2)[CH:17]=[N:18]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl hydrochloride salt (0.5 g, 1.63 mmol) in N,N-dimethylacetamide (5 mL) and water (2 mL). Add 4-acetamidophenylboronic acid (1.2 eq., 0.35 g, 1.96 mmol). Add tetrakis(triphenylphosphine)palladium(0) (0.01 eq., 0.019 g, 0.016 mmol). Add potassium carbonate (3.6 eq., 0.54 g, 3.9 mmol). Heat at 90° C. for 10 hr. Purify by normal phase chromatography with 6% 7N ammonia-methanol/ethyl acetate to give N-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-acetamide (0.25 g, 38%). MS (ES): m/z=406.2[M+H]. Dissolve this free base (0.25 g, 0.6 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.60 mmol, 0.60 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilize for 48 hr. to give the title compound salt (0.26 g, 99%). MS (ES): m/z=406.2[M+H].
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8].[OH-].[Na+]>C1COCC1.CO>[CH2:14]([O:13][C:11]([NH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[C@@H:5]([O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:4][C:3]([OH:32])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)[C@H](CC(=O)O)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 13 (2.2 g, 4.7 mmol) in 50 mL of THF/MeOH (1:1), cooled to 0° C., 1N NaOH solution (55 mL, 32 mmol) was added. The reaction was stirred at 0° C. for 2 h and then overnight at rt. The reaction mixture was concentrated and diluted with H2O (20 mL), cooled to 0° C., acidified to pH 2 with 1N KHSO4 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with NaCl (50 mL, sat), dried (Na2SO4), filtered and evaporated. The resulting acid 14 was obtained as a colorless oil (1.76 g, 86%) and used directly in the next step. 1H-NMR (500 MHz, CDCl3): 0.86 (m, 3H), 0.95 (d, J=6.7 Hz, 3H), 1.04-1.14 (m, 21H), 1.90-2.00 (m, 1H), 2.52-2.72 (m, 2H), 3.60-3.62 (m, 1H), 4.28-4.36 (m, 1H), 5.02 (d, J=10.4 Hz, 1H), 5.07-5.13 (m, 3H), 7.25-7.35 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH:30](Cl)[CH3:31]>CN(C=O)C>[Cl:29][CH2:30][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: CC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCl
Temperature: 70 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
7-Hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (85 g, 270 mmol, several batches pooled together) was dissolved in DMF (400 mL), potassium carbonate (77 g, 550 mmol) and dichloroethane (400 mL, 5130 mmol) were added and the reaction mixture was stirred overnight at 70° C. The solid was removed by filtration and washed with DMF. The solvent was evaporated and the solid so obtained was washed with water and dried at 50° C. over P2O5. The crude product was purified by flash chromatography using dichloromethane/ethyl acetate (85/15 up to 75/25). Evaporation of the solvent gave 7-(2-chloroethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (65.6 g, 66%) as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:31])([F:33])[F:32])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-(4-benzhydrylpiperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Br>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)OCc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 118.4 %

Procedure:
2-(2,6-Difluorophenyl)4-acetoxymethylbenzimidazole (Example 101) (3.55 g, 11.74 mmol) and 2,6-difluorobenzylbromide (3.40 g, 16.4 mmol, 140 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (5.94 g, 13.9 mmol, 76% yield). M.p. 126-127° C. 1HNMR (300 MHz, CD2Cl2): δ7.54 (m, 1H, H4′), 7.48 (m, 1H, H6), 7.33-7.27 (m, 2H, H5,7), 7.25 (m, 1H, H″), 7.08 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.54 (s, 2H, CH2PhF2), 5.36 )s, 2H, CH2O), 2.08 (s, 3H, OAc).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccncn3)cc(C)c21
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A mixture of [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.5 g, 1.38 mmol), 10% Pd/C (0.45 g) and K2CO3 (0.38 g, 2.75 mmol) in EtOAc (15 mL) was hydrogenated at 30 psi for 1.5 hours. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give [1-hydroxy-4-methyl-6-(pyrimidin-4-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.4 g, 88%). 1H NMR (400 MHz, DMSO): δ 9.27 (s, 1H), 8.73 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (d, J=6.8 Hz, 2H), 5.54 (dd, J=2.4, 9.2 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 3.13 (dd, J=2.4, 15.2 Hz, 1H), 2.34-2.27 (m, 1H), 2.30 (s, 3H), 1.13 (t, J=7.2 Hz, 3H). MS (ESI) m/z=329 [M+H]+.
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(Cl)cc2)N1
Yield: 51.1 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 0.83 mmol) was reacted with NaOH (60 mg, 1.49 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.2 g, 51%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH:4]=[C:3]([C:13]#[N:14])[CH:2]=1.[Cl-].[Li+].[N-:17]=[N+:18]=[N-:19].[Na+]>COC(O)C>[NH:14]1[C:13]([C:3]2[CH:4]=[C:5]([CH:6]=[CH:1][CH:2]=2)[CH2:7][C@@H:8]([C:9]([OH:11])=[O:10])[NH2:12])=[N:19][N:18]=[N:17]1
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: COC(C)O
Agent: [Cl-]
Agent: [Li+]
Product: N[C@@H](Cc1cccc(-c2nnn[nH]2)c1)C(=O)O
Temperature: 125 °C
Yield: 200.8 %

Procedure:
A suspension of L-3-cyano-phenylalanine (0.150 g, 0.79 mmol), lithium chloride (0.060 g, 1.43 mmol) and sodium azide (0.067 g, 1.03 mmol) in methoxyethanol (500 μL) was heated at 125° C. for 18 h. The solvent was evaporated to yield 370 mg of crude 3-tetrazolyl-L-phenylalanine.