Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[P:4](=[O:8])([OH:7])([OH:6])[OH:5]>>[OH2:5].[OH2:1].[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:2].[Ca+2:2]
Reactant: [OH-]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Product: O
Product: O=P([O-])([O-])[O-]

Procedure:
This material is typically produced by first reacting a slaked lime slurry with phosphoric acid to form a dicalcium phosphate dihydrate precipitate, and then separating the dicalcium phosphate dihydrate precipitate from the mother liquor after which it is dried and milled to form the final product as a fine powder.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN.C1C=CC2N(O)N=[N:43][C:41]=2C=1.C(N(C(C)C)CC)(C)C.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(#N)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([NH:43][CH3:41])=[O:24])[CH2:20][CH2:21]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer are introduced 1.5 g (3 mmoles) of {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetic acid (compound 229 prepared at example 1.4.2 above), 7 ml of THF and 7 ml of acetonitrile. Then 1.85 ml (3.7 mmoles) of a 2M solution of methylamine in THF are added, followed by 234 mg (1.5 mmoles) of HOBT, 1.33 ml (7.6 mmoles) of diisopropylethylamine and 880 mg (4.3 mmoles) of DCC. The mixture is stirred until completion of the reaction, and filtered. Volatile substances are removed under reduced pressure, and the residue is partitioned between ethyl acetate and 0.1 N sodium hydroxide. The organic phase is washed with brine, dried over magnesium sulfate and volatile substances are removed under reduced pressure. This yields crude 2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-N-methyl-acetamide (compound 292) which is directly converted into its dimaleate salt in 2-butanone (1.44 g of a white solid; yield 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@@H]2C3[CH:46]=[CH:47][S:48]C=3CC[C@H]2CCC)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:19]3[CH:46]=[CH:47][S:48][C:20]=3[CH2:22][CH2:21][C@H:26]2[CH2:25][CH2:24][CH3:23])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50, 7.35-7.31, 7.11, 6.91, 5.21, 4.59, 2.82, 2.64, 2.48, 2.05, 1.82, 1.43-1.35, 1.25, 1.18, 0.94; HRMS (FAB) calcd for C25H29Cl2N3S+H 474.1537, found 474.1526.
Reaction SMILES: [F:1][C:2]1[C:3](N)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.FC1N=C([Cl:17])C(F)=CN=1>O>[OH:8][C:5]1[N:4]=[C:3]([Cl:17])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: Fc1ncc(F)c(Cl)n1
Reactant: Nc1nc(=O)[nH]cc1F
Solvent: O
Product: Oc1ncc(F)c(Cl)n1

Procedure:
A process for the preparation of 5-fluorocytosine comprising reacting 2,5-difluoro-4-chloropyrimidine with a proton acid in the presence of water to yield 2-hydroxy-4-chloro-5-fluoropyrimidine, and reacting the 2-hydroxy-4-chloro-5-fluoropyrimidine with ammonia to yield 5-fluorocytosine.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:15])([CH3:3])[CH3:2].[CH2:16]([O:19][C:20]1[C:29]([CH3:30])=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][C:21]=1[CH3:31])[CH:17]=[CH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:16]([O:19][C:20]1[C:29]([CH3:30])=[CH:28][C:23]([C:24]2[N:26]=[C:9]([C:8]3[CH:7]=[C:6]([CH3:15])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:13]([CH3:14])[CH:12]=3)[O:11][N:25]=2)=[CH:22][C:21]=1[CH3:31])[CH:17]=[CH2:18]
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1C
Reactant: Cc1cc(C(=O)O)cc(C)c1OC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1c(C)cc(-c2noc(-c3cc(C)c(OC(C)C)c(C)c3)n2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
To a mixture of 4-isopropoxy-3,5-dimethyl-benzoic acid (175 mg, 794 μmol), 4-allyloxy-N-hydroxy-3,5-dimethyl-benzamidine (165 mg, 792 μmol) and DIPEA (128 mg, 993 μmol) in DCM (10 mL), TBTU (321 mg, 1.00 mmol) is added at 0° C. The mixture is stirred at 0° C. for 1 h, then at rt for 5 h, before it is diluted with EA (100 mL) and washed with sat. aq. NaHCO3 solution (2×30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The residue is dissolved in dioxane (10 mL) and stirred at 90° C. for 2 days. The solvent is evaporated and the residue is dried to give crude 3-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isopropoxy-3,5-dimethyl-phenyl)-[1,2,4]oxadiazole (346 mg); LC-MS: tR=1.25 min, [M+1]+=393.47.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[NH2:6][CH:7](CC)[CH:8]=O.[CH:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C(OCC)C>[CH2:14]1[CH:15]2[N:6]([CH2:2][CH2:1][C:3](=[O:4])[CH2:5]2)[CH2:12][CH2:13]1.[CH2:13]1[CH:14]2[N:6]([CH2:3][CH2:5][CH2:16][CH2:15]2)[CH2:7][CH2:8][C:12]1=[O:17]
Reactant: C=CC(C)=O
Reactant: CCC(N)C=O
Reactant: CCCCC=O
Solvent: CCOCC
Product: O=C1CCN2CCCC2C1
Product: O=C1CCN2CCCCC2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compounds of Formula (A) are prepared by acid treatment of the addition product of methyl vinyl ketone and an aminobutanal, pentanal, or hexanal dialkylacetal, such as diethyl acetal. The reaction is performed by first dissolving the appropriate aminoacetal in an appropriate solvent, typically diethyl ether at 0° C., and then adding approximately 1.7 equivalents of methyl vinyl ketone. Typically the reaction is allowed to stir at 0° C. for approximately 2 hours before acidification by addition of, or extraction with, aqueous hydrochloric acid. Typically, the organic layer is removed before heating the aqueous layer to approximately 100° C. for 1 hour. The resulting 7-octahydroindolizinone, 2-octahydro-2H-quinolizinone, or 4-(1-azabicyclo[5.4.0]undecan)ones (A) may be isolated from the reaction mixture by adjusting the pH of the solution to alkaline and extracting with a water immiscible solvent such as ethyl acetate or dichloromethane. The compounds recovered may be used directly in subsequent steps or first purified by silica gel chromatography or vacuum distillation.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH:18]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].ClC1C=CC(S(O[CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=O)=O)=CC=1.O>CS(C)=O>[C:21]1([CH2:20][O:19][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:18][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (36.0 mg, 1.50 mmol) was added to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 400 mg, 1.25 mmol) in dimethylsulfoxide (8 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. 1,1-Dimethylethyl (2S)-2-({[(4-chlorophenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (444 mg, 1.25 mmol) in dimethylsulfoxide (7 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product, which was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to yield the title compound as a yellow oil. 0.60 g.
Reaction SMILES: [I-].C[N+]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)=O)(C)C.[C:22]([O:25][CH2:26][CH3:27])(=O)C.[OH2:28]>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([CH:8]=[CH:7][C:6]([CH:7]=[CH:8][C:10]2[CH:27]=[C:26]([O:25][CH3:22])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[O:28])[CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19]
Reactant: CCOC(C)=O
Reactant: O
Reactant: COc1cc(C(=O)CC[N+](C)(C)C)cc(OC)c1OC
Agent: [I-]
Product: COc1cc(C=CC(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reaction time: 2.5 h

Procedure:
3-(N,N,N-trimethylammonio)-1-(3,4,5-trimethoxyphenyl)propan-1-one iodide (355.9 g, 0.87 mole) was suspended in a mixture of water (3.56 L) and of ethyl acetate (2.54 L) and refluxed with rapid stirring for 2-3 hours. The mixture was cooled and the pale yellow organic layer was removed. Fresh ethyl acetate (2 L) was added and the mixture was refluxed for 1 hour, and the process was repeated once again. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, and evaporated to dryness to provide a yellow oil, which was crystallized from hexane/ether to give 3,4,5-trimethoxyphenylvinyl ketone (m.p. 45°-47° C.). 200 MHz 1H NMR (CDCl3): δ 3.94 (9H, s, 3 OCH3), 5.92 (1H, dd, J=1.5 Hz, J=9 Hz), 6.44 (1H, dd, J=1.5 Hz, J=1.5 Hz, J=16 Hz), 7.18 (1H, dd, J=16 Hz, J=9 Hz), 7.28 (2H, H2 and H6).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:6][C:7]([Cl:11])=[N:8][C:9]=1[Cl:10])[CH:2]=C.C[N+]1([O-])CC[O:24]CC1>ClCCl.[Os](=O)(=O)(=O)=O>[Cl:11][C:7]1[N:8]=[C:9]([Cl:10])[C:4]([CH2:1][CH:2]=[O:24])=[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:6]=1
Reactant: C=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: O=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product from step (i) (2 g) in dichloromethane (40 ml) was added to a solution of osmium tetroxide (1 ml, 2.5% wt in isopropylalcohol) and 4-methylmorpholine N-oxide (1.12 g) in dichloromethane (1 ml). After stirring at room temperature for 24 h the mixture was washed with water, aqueous sodium sulphite solution, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in methanol (40 ml), cooled to 0° C. and lead tetraacetate (3.85 g) added. After 1 h the mixture was diluted with water, extracted with ethyl acetate, the organics dried (MgSO4) and evaporated under reduced pressure. Yield 2 g
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:11][C@@H:12]1[C@@H:24]([N:25]=[N+:26]=[N-:27])[C@@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21][C@H:13]1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:10])[CH3:9].CCCCCCC.[CH3:38][CH2:39][O:40]C(C)=O>N1C=CC=CC=1>[C:8]([O:11][C@@H:12]1[C@@H:24]([N:25]=[N+:26]=[N-:27])[C@@H:23]([O:28][C:1](=[O:3])[CH3:2])[C@@H:22]([CH2:29][O:30][C:39](=[O:40])[CH3:38])[O:21][C@H:13]1[S:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:10])[CH3:9]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])[C@@H](O)[C@@H](CO)O[C@H]1Sc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O

Procedure:
Acetic anhydride (30 mL) was added to a solution of compound 6 (373 mg, 1.1 mmol) in dry pyridine (30 mL). The reaction was monitored by TLC (heptane:EtOAc, 1:1) and when it was complete, it was concentrated under reduced pressure. 1H NMR in CDCl3 δ 7.54-7.51 (m, 2H, Ar), 7.35-7.30 (m, 3H, Ar), 5.46 (dd, 1H, H-4), 5.23 (t, 1H, H-2), 4.73 (d, 1H, H-1), 4.15 (d, 2H, H-6, H-6), 3.94 (dt, 1H, H-5), 3.68 (dd, 1H, H-3), 2.18 (s, 3H, OAc), 2.15 (s, 3H, OAc), 2.06 (s, 3H, OAc).
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:11](=[O:29])[CH2:10][CH2:9]1)(C)(=O)=O.C([O-])([O-])=O.[K+].[K+].[C:44]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>C(#N)C.CCOCC.CN(C=O)C>[ClH:36].[F:23][C:21]([F:24])([F:22])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1)[CH2:14][N:12]1[CH2:13][C:8]([CH2:7][CH2:6][N:53]2[CH2:54][CH2:55][CH:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:51][CH2:52]2)([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:9][CH2:10][C:11]1=[O:29]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CCC(CCN2CCC(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 22.3 %

Procedure:
2.79 g of 5-(2-mesyloxyethyl)-5-(3,4-dichlorophenyl)-1-[3,5-bis(trifluoromethyl)benzyl]piperid-2-one prepared in Example 1, step B, 1.95 g of K2CO3 and 0.91 g of 4-phenylpiperidine are mixed in 6 ml of acetonitrile and 6 ml of DMF and the mixture is heated at 80° C. for 4 hours. After evaporation of the solvents, the residue is extracted with ethyl acetate and the extract is washed with water and then with saturated NaCl solution. It is dried over MgSO4 and concentrated and the residue is then chromatographed on silica using DCM/MeOH (100/1; v/v) as the eluent. A sample of the product obtained is taken up with a solution of hydrochloric acid in ether and the solvent is evaporated off to give 0.365 g of the expected product, which crystallizes from a pentane/ether mixture. M.p.=170° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>C(#N)C>[F:14][C:13]([F:16])([F:15])[O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([CH2:2][NH:20][CH2:17][C:18]#[CH:19])[S:4][C:5]=2[CH:11]=1
Reactant: FC(F)(F)Oc1ccc2nc(CBr)sc2c1
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNCc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 85.9 %

Procedure:
2-(bromomethyl)-6-(trifluoromethoxy)benzo[d]thiazole (3.8 g, 0.0122 mol) and propargylamine (1.7 g, 2.5 eq) were dissolved in acetonitrile (50 ml) and the reaction mixture was heated to reflux for 1 h. Then it was cooled, evaporated to dryness and the residue was partitioned between EtOAc and water, 0.5 ml of NH4OH was add (pH=9-10) and the organic phase was separated, dried over Na2SO4, evaporated and the residue purified by chromatography (hexane-EtOAc) to give 3 g (86%) of N-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)methyl)prop-2-yn-1-amine. The free base was dissolved in 100 ml Et2O and HCl/IPA was added. The white suspension that was obtained was filtered and dried to give 2.7 g (mp=188-189° C., dec) of white solid, which was identified as the HCl salt of Compound B. 1H-NMR (of the HCl salt of the title compound, DMSOd6) δ 10.23 (br s, 2H, NH2), 8.35 (s, 1H, Ar), 8.16 (d, 1H, Ar), 7.57 (d, 1H, Ar), 4.76 (s, 2H, C—CH2) 4.04 (d, 2H, N—CH2—C), 3.74 (s, 1H, CH); 13C-NMR (DMSOd6) δ 164.40, 150.66, 145.74, 136.53, 124.01, 120.39, 120.10, 115.54, 79.84, 74.88, 46.05, 35.80; LCMS (ES-API for free base) 287.0 (M+H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C([N:8]([CH2:15][CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.N1C2C(=CC=CC=2)CC1=O.O>C1(C)C=CC=CC=1>[Cl:3][C:15]1[NH:8][C:9]2[C:10]([CH:16]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)c1ccccc1
Agent: O=C1Cc2ccccc2N1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
At room temperature, POCl3 (1 ml, 10.82 mmol, 2 eq) is added to a well stirred suspension of N,N-diethylaniline (1 ml, 5.41 mmol, 1 eq) and 1,3-dihydro-2H-indol-2-one x159 (0.72 g, 5.41 mmol, 1 eq) in dry toluene (15 ml). The mixture is heated at reflux during 3 hours. After cooling, water (15 ml) is carefully added and the organic layer is washed with water (3×25 ml). The organic layer is dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain 0.76 g of 2-chloro-1H-indole x160 as an orange solid (0.76 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH:11]=[CH:15][CH:14]=[CH:13]1
Reactant: Nc1ccccc1O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Oc1ccccc1-n1cccc1

Procedure:
109 g of o-aminophenol and 132 g of 2,5-dimethoxy-tetrahydrofurane in 700 ml of glacial acetic acid are heated to the boil for 30 minutes. After cooling, the reaction mixture is filtered and the polymeric material is thus removed. The filtrate is evaporated in vacuo, the residue is dissolved in approx. 1 liter of ethyl acetate and the solution is washed with 200 ml of water. The dark oil which remains after drying and evaporating the organic phase is distilled in a bulb tube under a high vacuum. This gives o-(pyrrol-1-yl)-phenol of boiling point 115°-125° C/0.05 mm Hg gives an oil which gradually crystallises and melts at 46°-49° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:13]2[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[N:15][N:14]=2)[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl>[Cl-:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:13]2[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[N:15][N:14]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)n1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)n1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: [Cl-]

Procedure:
A solution of the dried acid prepared in Step A in 20 mL of dry methylene chloride at room temperature was treated with 4 mL of oxalyl chloride (redistilled over CaH2). The mixture was refluxed under an argon atmosphere for two hours forming a light brownish solution. Most of the volatile solvents were evaporated under reduced pressure and the last traces of oxalyl choride were removed under high vacuum (0.01 mmHg) at room temperature for 12 hours to give the title compound.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[CH3:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[CH:30][C:29]=1[CH2:39][C:40]1[O:41][CH:42]=[CH:43][N:44]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(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>[CH3:25][C:22]1[C:21]([CH3:26])=[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[C:4]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][CH:36]=[CH:37][N:38]=4)=[CH:30][C:29]=3[CH2:39][C:40]3[O:41][CH:42]=[CH:43][N:44]=3)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:12])=[O:11])[O:24][N:23]=1
Reactant: Brc1ccc(-c2ncco2)cc1Cc1ncco1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1Cc1ncco1
Temperature: 75 °C

Procedure:
To a solution of 2-borono-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-benzenesulfonamide (472 mg, 1.3 mmol, prepared as described in Step (B) of Example 1), the title compound of Step (D) of this Example (250 mg, 0.82 mmol) in 8 ml of toluene and 6.4 ml of 95% EtOH under argon, tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) was added and followed by 4.8 ml of 2M aq. sodium carbonate. The reaction mixture was heated at 75° C. for 4 hrs, cooled and diluted with 50 ml of EtOAc. The organic liquid was separated and washed with 10 ml H2O and 10 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 1:2 hexane/EtOAc to afford the title compound of this step (47 mg, 10%) as a colorless gum. Rf=0.17, silica gel, 1:2 Hexane/EtOAc.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:20][OH:21].C(N(CC)C(C)C)(C)C.CC(O)=O>C(O)CCC>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:20][OH:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CC(=O)O
Product: ON=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 120 °C

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.35 g, 1.33 mmol; Example #23, Step B), hydroxylamine hydrochloride (0.46 g, 6.7 mmol), N,N-diisopropylethylamine (1.6 mL, 9.32 mmol) and AcOH (0.2 mL, 3.5 mmol) in n-butanol (20 mL) was heated at about 120° C. for about 18 h. Additional hydroxylamine hydrochloride (0.185 g, 2.66 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and AcOH (0.15 mL, 2.7 mmol) were added to the mixture and the reaction was heated at about 120° C. for about 18 h. Additional amounts of hydroxylamine hydrochloride (0.185 g, 2.66 mmol), DIEA (0.70 mL, 4.0 mmol), and AcOH (0.15 mL, 2.7 mmol) were added to the mixture and the reaction was heated at about 130° C. for about 3 days. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (3×40 mL) and brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in heptane gradient as the eluent to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone oxime as an off white solid (0.193 g, 52%): LC/MS (Table 2, Method a) Rt=2.22 min; m/z: 276 and 278 (M−H)−.