Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:46]1[CH2:47][CH2:48][CH2:49][CH:44]([CH2:43][OH:42])[CH2:45]1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: OCC1CCCNC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(N4CCCC(CO)C4)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (230 mg, 0.40 mmol) and 3-hydroxymethyl-piperidine (Aldrich, 1.20 g, 12.10 mmol) in DMF (6 ml) was treated with NaH (Aldrich, 146 mg, 6.08 mmol). After stirring for 30 minutes at room temperature and then 30 hours at 120° C. the mixture was cooled and poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate in hexanes gradient) and then further purified by HPLC (silica gel, 30% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane to give 6-fluoro-5-(3-hydroxymethyl-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 12 mg, 8%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:7]([F:20])[C@@H:6]1[OH:21])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:7]([F:20])[C@@H:6]1[OH:21]
Reactant: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@@H]2O[C@H](CN)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 82.1 %

Procedure:
A solution of 0.4 g of 1-(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 20 ml of ethanol was hydrogenated at room temperature and under atmospheric pressure in the presence of 0.1 g of 10% palladium-on-carbon catalyst for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with diethyl ether and the solid was removed by filtration, washed with ethyl acetate and dried in vacuo to give 0.3 g of 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([O:5][CH2:4][C@H:3]([CH3:6])[CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](CO)CBr
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H](C)CBr
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
5 g of (S)-(+)-3-bromo-2-methyl-1-propanol (32.6 mmol) were stirred in 5 ml of pyridine at room temperature. 3.67 g of acetic anhydride (35.9 mmol) were added and the reaction mixture was stirred for 3 h at 70° C. Stirring was continued for 16 h at room temperature. 30 ml of water and 40 ml of ethyl acetate were added. The organic layer was separated and washed with a further portion of water, then dried over magnesium sulfate, filtered, and evaporated under reduced pressure, whereby 4.34 g of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([N:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]([O:5][C:6](=[O:26])[C:7]([N:12]=[C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)(C(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2-(benzhydrylidene-amino)-hex-5-enoic acid tert-butyl ester (350 mg, 1 mmol) in THF (5 mL, 0.2 M) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.2 mL, 1.0 M, 2.2 equiv) drop wise over 5 min and stirred for 30 min. After adding benzoyl chloride (140 μl, 1.2 mmol, 1.2 eq), the reaction mixture was warmed up to room temperature and stirred for an additional 1.5 h. The solution was cooled to 0° C. and quenched with water (5 mL). The resulting solution was diluted with ethyl acetate and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-40% ethyl acetate in heptane gave 2-(benzhydrylidene-amino)-2-benzoyl-hex-5-enoic acid tert-butyl ester (477 mg, 1 mmol, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[C:8]=2[CH3:15])=[CH:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C:42]1[C:43](=[O:55])[N:44]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[N:45]([CH3:48])[C:46]=1[CH3:47].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:49]1([N:44]2[C:43](=[O:55])[C:42]([NH:41][C:12]([C:9]3[C:8]([CH3:15])=[C:7]([C:5]4[CH2:6][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]=4)[O:11][N:10]=3)=[O:14])=[C:46]([CH3:47])[N:45]2[CH3:48])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: Cc1c(C(=O)O)noc1C1=CCC(C)(C)C1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(4,4-dimethylcyclopent-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (105 mg, 0.475 mmol) in dry NMP (3 mL), HATU (198 mg, 0.522 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (109 mg, 0.522 mmol) and triethylamine (0.146 mL, 1.044 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (aq) (20 mL) and the organic phase was washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-60% EtOAc in iso-hexane afforded crude material. The crude material was dissolved in DMSO and purified using mass-directed automated reverse phase chromatography over a 9.5 minute gradient of 40-80% MeCN in water (0.1% formic acid). The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: C1(C2CCN(C[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH:28]([OH:29])[C:27]4[CH:30]=[CH:31][CH:32]=[C:25]5[C:26]=4[C:21](=[CH:22][CH:23]=[CH:24]5)[C:20]3=[O:33])CC=2)C=CC=CC=1.[Br:34]CCCCCBr.BrCCCCCCBr>>[Br:34][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[C:25]3[C:26]=2[C:21](=[CH:22][CH:23]=[CH:24]3)[C:20]1=[O:33]
Reactant: BrCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(O)N1CCCCCCN1CC=C(c2ccccc2)CC1
Agent: BrCCCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 4 but substituting 1,5-dibromopentane for the 1,6-dibromohexane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[P:8]([OH:11])([OH:10])[OH:9].P(Cl)(Cl)Cl.C>C1(OC2C=CC=CC=2)C=CC=CC=1.CO.C1(C)C=CC=CC=1.O>[CH2:3]([CH2:2][NH2:1])[CH2:4][C:5]([P:8]([OH:11])([OH:10])=[O:9])([P:8]([OH:11])([OH:10])=[O:9])[OH:7]
Reactant: OP(O)O
Reactant: NCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C

Procedure:
The suspension of 4-amino butyric acid (10.0 g) and phosphorous acid (23.9 g) in diphenyl ether (50 ml) was heated up to 70° C. for 1 hour. Phosphorous trichloride (25.4 ml) was slowly added to reaction mass at 70° C. temperature and maintained reaction temperature for another 6 hours. Reaction mass was cooled to 25° C. followed by addition of water (150 ml) and toluene (30 ml). Reaction mixture was again heated to 70° C. and charged charcoal in hazy biphasic solution, stirred, filtered through Hyflo bed, washed the bed with hot water (30 ml). Layers was separated from filtrate, aqueous layer was washed with toluene (20 ml) and combined organic layer was then back extracted with water (20 ml) and mixed with main aqueous layer. The water (140 ml) was distilled out from combined aqueous layer at atmospheric pressure in 2 hours and then refluxed the concentrated mass for 13 hours. Reaction mass was cooled to 25° C. followed by addition of methanol (150 ml) in 1 hours. The reaction mixture was stirred and again cooled to 0° C. followed filtration. The filtrate was washed with chilled 1:2 mixture (30 ml) of water and methanol and dried at 60° C. to get Alendronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([S:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+]([O-])=O)=C[CH:31]=1)=[O:28].N1C=CC=CC=1.C1([C@H](O)C)CC1>CCOC(C)=O.ClCCCl>[CH:35]1([C@H:30]([O:29][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([S:19][CH2:20][CH3:21])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:31])[CH2:34][CH2:33]1
Reactant: CCSc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)C1CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCSc1ccc2c(C#N)c(-c3ccc(NC(=O)O[C@H](C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To 2-(4-amino-phenyl)-1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (230.0 mg, 0.66 mmol) was combined with p-nitrophenyl chloroformate (266 mg, 1.32 mmol), DCE (3.0 mL), and pyridine (104.7 mg, 1.32 mmol) and stirred at room temperature for 2 h. (R)-1-Cyclopropylethanol (115.0, 1.34 mmol) was added and mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. aq. K2CO3 (2×15 mL), water, and brine. The organic layer was dried, concentrated and purified on silica gel (EtOAc/hexane 10%)) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-ethylsulfanyl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (209 mg, 69%) as a white solid.
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.C1(N)CCCC1.[CH2:27]([O:29][C@@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C@@H:42]([C:44](=[O:61])[NH:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52]C(OC3C=CC=CC=3)=CC=2)C)=[CH:37][CH:36]=1)[C:31]([OH:33])=[O:32])C>>[CH:46]1([NH:45][C:44]([CH2:42][O:41][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][C@H:30]([O:29][CH3:27])[C:31]([OH:33])=[O:32])=[CH:40][CH:39]=2)=[O:61])[CH2:47][CH2:48][CH2:53][CH2:52]1
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: NC1CCCC1
Product: CO[C@@H](Cc1ccc(OCC(=O)NC2CCCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and cyclopentylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C17H23NO5 [M−H]−: 320.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[NH:12][C:13](=O)[C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.O>CN(C)C=O>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:13]2[NH:12][C:3]3[C:4](=[O:11])[NH:5][C:6](=[O:10])[N:7]([CH2:8][CH3:9])[C:2]=3[N:1]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCn1c(N)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(=O)[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
To a stirred solution of 3-(3,4-dimethoxyphenyl)propynoic acid (6-amino-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) amide (2.27 g, 6.3 mmol) in 12 ml of dry dimethylformamide was added phosphorous pentaoxyde (5 g, 17 mmol). The mixture was stirred at 100° C. for 10 min and cooled to room temperature. The product was recipitated by adding water (100 ml), filtered under reduced pressure, washed thoroughly with water and dryed at 70° C., light yellow yielding 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-3,7-dihydro-purine-2,6-dione (1.6 g, 74%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>CN1CCCC1=O>[CH3:20][C:9]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=[C:2]([NH:27][CH:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[N:7]2[N:8]=1
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Reactant: CCC(N)CC
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 125 °C

Procedure:
A mixture of 7-Chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (60 mg, 0.2 mmol) and 1-ethylpropylamine (4 ml) in 1 ml of N-methylpyrro-lidinone was heated at 125° C. oil bath for 15 hrs. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give 35 mg of the title compound as a yellow solid. 1H NMR (CDCl3) ä 6.96(s, 2H), 6.00(d, 1H), 5.77(s, 1)H, 3.47 (m, 1H), 2.43(s, 3H), 2.32(s, 3H), 2.22(s, 3H), 2.05(s, 6H), 1.5-1.9(m, 4H), 1.04(t, 6H) ppm.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH3:49])=[C:37]([OH:50])[C:36]3=[O:51])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH3:49])=[C:37]([O:50][CH3:3])[C:36]3=[O:51])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CCC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: CCC1=C(OC)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/5 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-4-ethyl-5-(2,3-difluorophenyl)-3-hydroxy-1H-pyrrol-2(5H)-one (1.2 g, 2.81 mmol, 1 eq) and MeOH (10 ml), the product was further purified by preparative HPLC; yield: 0.085 g (8.2%); MS m/z: 370.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.01 (t, 3H), 1.94 (m, 1H), 2.39 (m, 1H), 3.96 (s, 3H), 6.24 (s, 1H), 7.12 (s, 1H), 7.55-7.26 (m, 3H), 7.67 (s, 1H), 8.17 (s, 1H), 12.43 (s, 1H); HPLC (METHOD [A]): rt 13.32 min (100%)
Reaction SMILES: C([NH:8][CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(Cl)Cl>CO.[OH-].[Pd+2].[OH-]>[O:13]1[C:12]2([CH2:17][CH2:18][CH:9]([NH2:8])[CH2:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.5 %

Procedure:
A mixture of N-benzyl-1,4-dioxaspiro[4.5]decan-8-amine (3 g, 12.2 mmol) and Palladium hydroxide (0.9 g) in MeOH (120 mL) was hydrogenated under 50 psi of H2 at room temperature. The mixture was stirred at room temperature for 24 h. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was filtered and the filtrated was concentrated in vacuo to give 1,4-dioxaspiro[4.5]decan-8-amine (2.1 g, 110%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)=[O:4].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([OH:26])=[CH:21][CH:20]=2.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:16])=[CH:25]2)=[O:4]
Reactant: COC(=O)c1cn2ncnc(Cl)c2c1C
Reactant: Cc1cc2cc(O)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (0.5 g, 2.22 mmol) and 2-methyl-5-hydroxyindole (424 mg, 2.9 mmol) under argon in acetonitrile (10.0 mL) was added triethylamine (6.65 mmol, 0.93 mL). After stirring the mixture at room temperature for 17 h. solvent was removed under vacuum and the residue was chromatographed on silica gel eluting with 20-30% ethyl acetate (gradient) in hexanes. The solvent was removed in vacuo to obtain 5-methyl-4-(2-methyl-1H-indol-5-yloxy)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester as a white solid (0.58 g, 85%). LC/MS; (M+H)+=337.2
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[NH:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[N:24]1[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CCl)c1
Reactant: CC1CCCC(C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2C(C)CCCC2C)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
A mixture of 66.69A (0.094 g, 0.30 mmol), 2,6-dimethylpiperidine (0.069 g, 0.61 mmol) (commercially available from Aldrich) and cesium carbonate (0.20 g, 0.61 mmol) in DMSO (4 mL) was stirred at 70° C. for 24 hours. The product was purified by reverse phase HPLC to give 66.69B in 30% yield.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[O-:7]S([O-])(=O)=O.[Na+].[Na+].[Na+].[Cl-]>>[OH2:2].[OH2:7].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5]
Reactant: O=S(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: O

Procedure:
In this comparative example, the sodium carbonate solution designated as stream 3 in Example 1, containing 27.2 wt % Na2CO3, 2.6 wt % Na2SO4 and 2.6 wt % NaCl, is subjected to a cooling crystallization at 20° C. to form sodium carbonate decahydrate. In the cooling crystallization, 376 kg/hr of feed solution are introduced to the crystallizer to yield centrifuged, damp sodium carbonate decahydrate at a rate of 250 kg/hr, of which about 5% is mother liquor. The mother liquor composition is about 13.1 wt % Na2CO3, 9 wt % Na2SO4 and 9 wt % NaCl.
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH:22]1[C:27]([C:28]([CH2:30][Br:31])=[O:29])=[CH:26][CH:25]=[C:24]([F:32])[CH:23]=1.Cl>C(OC)(C)(C)C>[Br:31][CH2:30][C@H:28]([C:27]1[CH:26]=[CH:25][C:24]([F:32])=[CH:23][CH:22]=1)[OH:29]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: COC(C)(C)C
Product: O[C@H](CBr)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, charge a 30 liter round bottom flask with a solution of (S)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 M in toluene; 44 mL; 44 mmol) at 22° C. Add a solution of borane-N,N-diethylaniline complex (1230 g; 7540 mmol) in methyl t-butyl ether (4.5 L). Heat and maintain the mixture at 40° C. for 30 min. Add a solution of bromo-4-fluoroacetophenone (1640 g; 7530 mmol) in methyl t-butyl ether (4.5 L) drop-wise over 30 min. Stir the mixture at 40° C. for 2 hours. Cool to 10° C. using an ice water bath; then slowly add MeOH (590 mL) to quench the reaction. Stir the mixture for 30 min while maintaining it at 10-20° C. Add hydrochloric acid (3.0 M, 7.5 L) to the mixture while it is at 10° C. Stir for one hour and filter. Collect the filtrate. Separate the layers in the filtrate; extract the aqueous phase with methyl tert-butyl ether (1×3 L); combine the organic phases and wash with brine; dry over Na2SO4; and filter; and remove the volatiles from the filtrate under reduced pressure to give the title compound as a pale yellow oil (1650 g, 99%). MS (m/z): 201 (M-OH); ee value: 97.5% (AD-H 250 mm×4.6 mm×5 μm column using 99:1 hexanes:EtOH at 25° C. with a flow rate of 1.0 mL/min).
Reaction SMILES: [H][H].[C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCC#Cc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: OCCCc1ccccc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 6, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 3-phenyl-2-propin-1-ol as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 3-phenyl-2-propin-1-ol, and 3-phenyl-1-propanol was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:2]2[CH:12]=[N:11][C:5]3[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=3[CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=C1COc2ncc(Br)cc2N1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1COc2ncc(C3CC3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a 10 ml flask, 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (400 mg, 1.746 mmol), cyclopropyl boronic acid (165 mg, 1.921 mmol), palladium acetate (39.1 mg, 0.174 mmol), triphenylphosphine (91.5 mg, 0.349 mmol) and potassium carbonate (482.6 mg, 3.492 mmol) were dissolved in a solvent of acetonitrile/water (6/1, 4.2 ml/0.9 ml). The reaction mixture was stirred for 60 minutes at 100□ using microwave (100 W) apparatus. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane and ethyl acetate. The fractions containing the product were collected and evaporated to obtain a mixture (40 mg, 0.8%) containing triphenyl phosphoxide.