Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=S(Cl)Cl.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH:11]3[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12]3)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CN1C2C=C(c3ccc(Cl)c(Cl)c3)CC1CC2
Reaction time: 17 h
Yield: 53 %

Procedure:
To 2.35 g (8.76 mmol) of 3-(3,4-dichloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol in 50 mL of Cl(CH2)2Cl is added 1.92 mL (3.13 g, 26.67 mmol) SOCl2. After stirring at 23 C for 17 h, the reaction mixture is poured into 5 N NaOH, extracted with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and extracted to give a brown oil. Flash chromatography on SiO2, eluting with CHCl3/MeOH (40/1 to 10/1) gives 1.24 g (4.62 mmol, a 53% yield) of the title compound as an orange oil. MS (ES) m/z 269 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:23]1(=O)[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12

Procedure:
The material prepared in Example 1A (250 g, 1.19 mole) was combined with zinc chloride (243.5 g, 1.784 mole) and toluene (3.75 L). The reaction mixture was heated to reflux under a nitrogen atmosphere. Benzoquinone (167 g, 1.546 mole) in tetrahydrofuran (500 mL) was added dropwise to the reaction, and upon completion of the addition, the reaction mixture was heated at reflux for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to a brown solid. The solid was recrystallized from acetonitrile yielding the title compound as a brown solid (125 g, 35%). MS m/z 301 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].[OH-].[Na+]>O>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSc1ccccc1
Temperature: 0 °C
Yield: 70.3 %

Procedure:
6.0 g of thiophenol and 7.8 g of 3-bromo-1-chloropropane were placed in 40 ml of water, and the resultant solution was subjected to reflux for 1 hour under heating. Then, 40 ml of an aqueous solution containing 2.4 g of sodium hydroxide were fed dropwise to the solution. The solution was then further subjected to reflux for another 2 hours under heating. The solution reacted was then poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer resulted was then washed with dilute aqueous alkaline solution and saturated saline solution in series, and the organic layer resulted was dried with anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, and the residue obtained was then purified by using silica gel column chromatography, for which hexane was used for the developer, thereby affording 6.5 g of 1-chloro-3-phenylthio propane.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.0 g, 26.7 mmol) and Et3N (8.0 g, 80.2 mmol) were dissolved in dichloromethane (50 mL). The mixture was stirred at 0° C. for 30 minutes, then methanesulfonyl chloride (4.5 g, 40.1 mmol) was added dropwise. It was stirred at room temperature for 2 h and concentrated under reduced pressure. DCM (50 mL) and water (50 mL) were added. The organic phase was washed with saturated NaHCO3 (30 mL) and H2O (2×30 mL), and concentrated to afford the title compound as oil (6 g, 100%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -15 °C
Yield: 91.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at -20 to -30° C. was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20° C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ˜600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.27 (m, 1 H), 3.44-3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15]>CC(C)=O>[C:14]([CH2:16][C:17]([NH:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9])=[O:18])#[N:15]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: N#CCC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: Cn1c(N)c(NC(=O)CC#N)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 5,6-diamino-1,3-dimethyluracil hydrate (19.0 g, 0.11 mole) and cyanoacetic acid (19.0 g, 0.22 mole) is heated to 120°-130° C. under a nitrogen atmosphere. The mixture melts and resolidifies within thirty minutes. The resolidified residue is cooled to room temperature and is taken up in acetone. The residue is collected on a filter, recrystallized in water using decolorizing carbon, dried, and triturated under vacuum to yield 5-cyanoacetamido-6-amino-1,3-dimethyluracil as a solid (14.2 g; 54%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Temperature: 140 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of 3-nitrobenzyl bromide (648 mg, 3.00 mmol) and triethyl phosphite (0.669 mL, 3.90 mmol) was stirred at 140° C. under nitrogen for 16 h. The excess triethyl phosphite was removed under reduced pressure and the residue purified by chromatography over silica gel eluting with 2% MeOH in dichloromethane to afford diethyl (3-nitrobenzyl)phosphonate, 0.80 g (yield: 98%). 1H-NMR (CD3OD, 400 MHz): δ=1.27 (t, J=6.8 Hz, 6 H), 3.43 (d, J=22.0 Hz, 2 H), 4.08 (q, J=6.8 Hz, 4 H), 7.58 (t, J=8.0 Hz, 1 H), 7.72 (d, J=7.6 Hz, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 8.22 (d, J=2.4 Hz, 1 H). MS (ES+): m/z 273.99 (MH+). HPLC: tR=2.92 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])=[CH:5]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12

Procedure:
Tryptamine (3.04 g, 19.0 mmol) and phthalic anhydride (3.00 g, 20.0 mmol) were boiled for 12 h in a water separator. The solvent was distilled off i. vac. and the residue was dissolved in methylene chloride. Product was precipitated out by addition of cyclohexane and the precipitate was filtered off with suction and dried. Yield: 4.46 g (Ind-1; 87%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CC([O-])(C)C.[K+].CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1cc2cccnc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by t-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoro-methyl-)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 35) (500 mg, 0.84 mmol) in dimethylformamide (7.0 ml) is added bis(triphenylphosphine)palladium(II) chloride (117.3 mg, 0.17 mmol), ethyl acrylate (457.2 μl, 4.18 mmol) and triethylamine (232.9 μl, 1.67 mmol). The reaction is stirred overnight (16 h) at 120° C., then cooled to room temperature, diluted with dimethylformamide (8 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→10:10). The title compound, which is still slightly impure, is isolated (356 mg) and then chromatographed again over silica gel 60 with cyclo-hexane/ethyl acetate (5:1) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9](OC)=[O:10])=[CH:4][CH:3]=1.[NH2:15][OH:16].CO[Na]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH2:8][C:9]([NH:15][OH:16])=[O:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CSCc1ccc(Cl)cc1
Agent: CO[Na]
Solvent: CO
Product: O=C(CSCc1ccc(Cl)cc1)NO

Procedure:
A solution of 0.15 mol of methyl p-chlorobenzylmercapto-acetate in 50 ml of methanol is mixed with a solution of 0.225 mol of hydroxylamine (base) and 0.15 mol of CH3ONa in 150 ml of methanol.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].Cl>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice:4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, bp-102°-104° C. (80 mm), pmr spectrum (CDCl3): δ 2.55 (triplet, --CH2CO--).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].B([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C#N)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
4-bromo-3-methylbenzonitrile (5 g, 0.026 mol) was suspended in 1,2-dimethoxyethane (100 ml) and treated with 4-boronobenzoic acid (2.4 g, 0.026 mol) followed by a solution of sodium carbonate (11.65 g, 0.11 mmol) in water (100 ml). The mixture was flushed with argon and tetrakis(triphenylphosphine)palladium (0) (0.55 g) was added. The reaction mixture was then heated to reflux with stirring. After 24 h, the 1,2-dimethoxyethane was removed by evaporation under reduced pressure and the aqueous residue was washed with ethyl acetate. The aqueous layer was then acidified to pH 1 and the resultant solid was filtered off and was dried in vacuo to give the title compound as a white solid (4.16 g, 69%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cccc(CN2CCCCC2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (25 g, 135 mmol) in dichloromethane (500 ml) was slowly added piperidine (12.6 g, 149 mmol) at 10° C. After stirring for 15 minutes at 10° C., acetic acid (8.9 g, 149 mmol) was added, followed by the portionwise addition of sodium triacetoxyborohydride, while the temperature was kept at 5-10° C. After stirring for 2 h at room temperature the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted into dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography afforded 2-bromo-6-(piperidin-1-ylmethyl)pyridine (30 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[CH:22]1([C:25]#[CH:26])[CH2:24][CH2:23]1.C(NC(C)C)(C)C>[Cu]I.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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16]([C:26]#[C:25][CH:22]3[CH2:24][CH2:23]3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(C#CC3CC3)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A vial was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (1.00 g, 2.88 mmol), cyclopropyl acetylene (0.732 mL, 8.64 mmol), copper(i) iodide (0.110 g, 0.576 mmol), and diisopropylamine (14.40 mL). tetrakis(triphenylphosphine)palladium(0) (0.333 g, 0.288 mmol) was added, the vial was flushed with argon, and the reaction was heated to 50° C. and stirred overnight. The reaction was diluted with ethyl acetate and filtered through Celite. The solution was concentrated and purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) to afford (S)-2-amino-2′-(cyclopropylethynyl)-5H-spiro[oxazole-4,9′-xanthen]-7′-ol as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]>CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Br)ccc1CO
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol) in Et2O (15 mL) was added lithium aluminumhydride (370 mg, 10.23 mmol) and the mixture was stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound as a colorless gum (752 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.35-7.30 (2H, m), 7.24 (1H, m), 4.65 (2H, s), 2.32 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>C(C(C)=O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 27 °C

Procedure:
A solution of esomeprazole (19.5 g, 56.5 mmol; 1.3% sulfone, 1.05% R-enantiomer) in methyl ethyl ketone (120 mL) was cooled to 15° C. 30% sodium methoxide in methanol (10.7 mL, 57.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 27° C. A solid started to crystallize. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with methyl ethyl ketone (2×20 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 12.4 g (60%). Sulfone content: 0.06%. R-enantiomer content: 0.00%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>CC(C)=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 28 °C

Procedure:
A solution of esomeprazole (5.3 g, 15.3 mmol; 1.3% sulfone, 1.05% R-enantiomer) in acetone (33 mL) was cooled to 15° C. 30% sodium methoxide in methanol (2.9 mL, 15.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 28° C. A solid started to crystallize. After 30 min stirring, methyl tert-butyl ether (6 mL) was added dropwise. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2×6 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 3.5 g (62%). Sulfone content: 0.28%. R-enantiomer content: 0.17%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (100 mg, 0.552 mmol) in methylene chloride (5 mL) was added thiophene-2-carbaldehyde (62 mg, 0.552 mmol), sodium triacetoxyborohydride (351 mg, 1.66 mmol) and drop of acetic acid. The solution was stirred for 4 hr. The solvent was removed under vacuum, and the crude product was loaded on a Isco 12 g column. Elution with 0% to 10% methanol in methylene chloride over 15 column volumes afforded the title compound (95 mg, 61% yield). Exact mass calculated for C13H15N3O2S 277.3. found 278.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.58 (d, J=5.05 Hz, 1H) 7.33 (d, J=3.03 Hz, 1H) 7.07-7.16 (m, 1H) 4.63 (s, 2H) 4.47 (s, 2H) 4.24 (s, 2H) 3.94 (t, J=5.56 Hz, 2H) 2.73 (t, J=5.56 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>C1C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCC(F)(F)F
Reaction time: 20 h

Procedure:
4,4,4-Trifluorobutyric acid (5.8 g, 0.041 mole) was dissolved in benzene (30 ml). Oxalyl chloride (6.2 g, 0.049 mole) was added and the reaction stirred for 20 hrs. The benzene and excess oxalyl chloride was removed by distillation to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([F:30])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1>CN1CCCC1=O.[Pd]>[F:30][C:21]1[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH3:29])[NH:25]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reaction time: 3.5 h

Procedure:
7-(Benzyloxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (40 kg) was dissolved in 1-methyl-2-pyrrolidinone (206 kg) at 40-45° C. This solution was charged to an inerted pressure vessel containing 10% palladium on carbon catalyst (0.235 kg of approximately 50% water wet catalyst). A line wash of 1-methyl-2-pyrrolidinone at 40-45° C. (35 kg) was applied. The mixture was hydrogenated at 45° C. and 3 barg for 3.5 hours. The reactor was purged with nitrogen and recirculated through a Gaf filter before being filtered through a 1 μm Pall filter into a new reactor. A line wash of 1-methyl-2-pyrrolidinone (66 kg) through the filters was applied to give a solution of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol. To this solution was added potassium carbonate (10.3 kg) and the mixture heated to 80° C.