Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C1COCC1>[Br:38][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
Cool (10° C.) a solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (Example 2, 753 mg, 3 mmol) in THF (12 mL) add triphenylphosphine (864 mg, 3.3 mmol) followed by freshly recrystallized N-bromosuccinimide (587 mg, 3.3 mmol). On complete addition, remove the cold bath and stir continuously for 45 min. Concentrate the resulting mixture under vacuum and purify the residue by flash chromatography (elute with 10% ethyl acetate/10% dichloromethane in heptane) to give the title compound as an orange solid (846 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:19]([O:23][C:24](=[O:44])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[CH2:34][NH:35][C:36]([C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][NH:39]1)=[O:37])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([N:39]1[CH2:40][CH2:41][O:42][CH2:43][C@H:38]1[C:36](=[O:37])[NH:35][CH2:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:44])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
To a solution of (R)-2-acetoxy-3,3-dimethylbutanoic acid (0.14 g, 1.04 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (1.10 mL, 1.30 mmol) at 0° C. under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated to dryness and the residue was dissolved in CH2Cl2 (4 mL). A solution of (S)-tert-Butyl-4-chloro-2-{(morpholine-3-carboxamido)methyl}benzylcarbamate (0.20 g, 0.52 mmol) and triethylamine (0.70 mL, 2.08 mmol) in CH2Cl2 (2 mL) was added dropwise at 0° C. and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with saturated NaHCO3 solution (10 mL) and 1M aqueous HCl (10 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil (0.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21](Br)C#C.CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:21])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
3.50 g (11.81 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) and 1.97 ml (17.71 mmol) of propargyl bromide were dissolved in 60 ml of acetonitrile and 3 ml of MeOH and treated with 6.62 g (14.17 mmol) Cs2CO3. After vigorous stirring for 3 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in EtOAc. The organic phase was washed with aqueous 1N NaOH (two times) and aqueous 10% NaCl. After extraction of the water phases with EtOAc (two times), the organic phase was dried (Na2SO4) and evaporated to give 3.48 g of the title compound as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O.S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([NH:6][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[CH3:7]
Reactant: COC(=O)[C@H](C)N
Reactant: COC(C=O)OC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)[C@H](C)NCC(OC)OC
Yield: 80.3 %

Procedure:
To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in MeOH (100 mL) were added at 0° C. dimethoxyacetaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0° C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6].[OH-].[Li+].Cl>C1CCC(O)CC1.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: OC1CCCCC1
Solvent: O
Product: CC(Oc1ccc(F)cc1F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To the solution of methyl 4-(1-(2,4-difluorophenoxy)ethyl)benzoate (151 mg, 0.54 mmol) in meth anol/water (50 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent and the residue was purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=5:1) to give 4-(1-(2,4-difluorophenoxy)ethyl)benzoic acid (127 mg, 88%)
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(-c2ccccc2)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: O
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(-c3ccccc3)c12
Yield: 21.4 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 86 mg (0.16 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-phenyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 17-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was applied to silica gel column chromatography (Eluent; ethyl acetate), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 14 mg of the title compound as a pale beige solid. (Yield: 21%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C(Cl)CCl.C1C=[N:30]C2N(O)N=NC=2C=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:30])=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20]
Reactant: CNc1ccc(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-[4-(methylamino)-3-nitrophenoxy]pyridine carboxylic acid in tetrahydro-furan was added EDC (2 eq) and HOAT (1.5 eq) and ammonium chloride (2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethylacetate and water. A solid crashes out in the aqueous layer which was filtered and was found to be the product on LC/MS. The organic layer was then dried with sodium sulfate and concentrated. Purification on silica gel gave 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:18]#[N:19]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:5][C:4]=1[C:18]#[N:19]
Reactant: CC(C)(C)NCC(=O)c1cc(F)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)(C)NCC(O)c1cc(F)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 242°-243° C. (decomp.), was prepared from 4'-amino-2-tert.butylamino-3'-cyano-5'-fluoroacetophenone analogous to Example 49.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([CH3:15])[NH:10]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:7][C:4]1[S:3][C:2]([N:13]2[CH2:12][CH:11]([CH3:15])[NH:10][CH:9]([CH3:8])[CH2:14]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2ncc(Br)s2)CC(C)N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
A mixture of 2,5-dibromothiazole (29.5 g), 2,6-dimethyl piperazine (13.8 g), potassium carbonate (20.1 g) and dimethylformamide (150 mL) was stirred at 60° C. for 6 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound (21.5 g). Yield: 64%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2I)[C:24](=[O:30])[C:25]#[C:26][CH:27]([CH3:29])[CH3:28])[CH:17]=1>>[CH3:13][O:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:25](=[C:26](\[C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)/[CH:27]([CH3:29])[CH3:28])/[C:24]2=[O:30])[CH:17]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C(C)=O)cc3)C(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-acetyl-phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.03-8.11 (m, 4H), 7.94 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.40 (t, 1H), 7.29 (d, 2H), 7.00 (t, 1H), 6.61 (d, 1H), 6.54 (t, 1H), 5.61 (d, H), 5.02-5.07 (m, 3H), 3.90 (s, 3H), 2.70 (s, 3H), 1.19 (d, 3H), 1.17 (d, 3H).
Reaction SMILES: NC1C(C(O)=O)=CN(C2N=CC3CC[C:14]4[CH:20]=[C:21]([O:24][CH3:25])C=C[C:13]=4[C:12]=3[N:11]=2)N=1.Br[C:27]1[CH:39]=[CH:38][C:30]2[NH:31]C(C(Cl)(Cl)Cl)=[N:33][C:29]=2[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.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>[NH2:33][C:29]1[CH:28]=[C:27]([C:20]2[C:21]([O:24][CH3:25])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:39]=[CH:38][C:30]=1[NH2:31]
Reactant: ClC(Cl)(Cl)c1nc2cc(Br)ccc2[nH]1
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1ccc(N)c(N)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-o-phenylenediamine 1 (0.935 g, 5 mmol), 2-methoxy-3-pyridyl boronic acid 2 and Na2CO3 (1.060 g, 10 mmols) in 1,4-dioxane/H2O (3:1, 20 mL) flushed with N2 was added Pd(PPh3)4 (0.575 g, 0.5 mmol) in one portion. Resulting reaction mixture was stirred under N2 atmosphere at 100° C. for 12 h. Solvent was evaporated and residue was extracted with ethyl acetate (20 mL). Dried over anhydrous sodiumsulfate. Filtered, and evaporation of solvent gave a crude residue which was used as such in the following reaction. (0.850 g).
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH3:3].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(CC)=O>[CH2:17]([NH:21][C:22]([NH:16][S:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])(=[O:14])=[O:15])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=O
Reactant: CC(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[(1-methylethyl)sulfonyl]benzenesulfonamide (29 g, 0.11 mol), n-butylisocyanate (14.7 g, 0.15 mol) and anhydrous potassium carbonate (16.6 g, 0.120 mol) in methylethyl ketone (325 ml) was refluxed with stirring for 3 hours. The reaction mixture was cooled to 0° and then poured into ice-water. The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to give N-[butylaminocarbonyl]-2-[(1-methylethyl)sulfonyl]benzenesulfonamide, m.p. 164.5°-165.5°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CC#N.[C:13](=[S:22])(Cl)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:13](=[S:22])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nc(=O)n(C(=S)Oc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 1.33 h
Yield: 29.6 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (99.7 mg, 0.772 mmol) and CH3CN (3 mL). BSA (0.284 mL, 1.16 mmol) was added, the vial was capped and the resulting heterogenous mixture was agitated on a rotary shaker at 65° C. for 80 min. The resulting clear and colorless solution was cooled to room temperature. O-Phenyl carbonochloridothioate (0.118 mL, 0.853 mmol) was added, and the reaction was agitated on a rotary shaker at 65° C. for 15 h. After cooling to room temperature, the crude material was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous sodium chloride (satd aq NaCl) solution (50 mL×2). The organic solution was then dried over Na2SO4, filtered, and concentrated in vacuo. The green/brown residue was then purified by normal phase chromatography (gradient, 0 to 35% methyl alcohol (MeOH)/CH2Cl2) to afford O-phenyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carbothioate (60.7 mg, 30%) as an 85% pure brown solid: mp 113-116° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 7.56-7.48 (m, 2H), 7.40-7.33 (m, 1H), 7.27-7.21 (m, 2H); ESIMS m/z 266 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[OH:13][CH2:14][CH2:15]O>C1(C)C=CC=CC=1>[O:12]1[C:2]2([CH2:3][CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]3)[CH2:1]2)[O:13][CH2:14][CH2:15]1
Reactant: OCCO
Reactant: O=C1CCCC2(C=CCCC2)C1
Solvent: Cc1ccccc1
Product: C1=CC2(CCC1)CCCC1(C2)OCCO1
Yield: 95 %

Procedure:
To a solution of the relevant spiro[5.5]undec-7-en-2-one isomer (10) or (10′) (10 g, 61 mmol) in toluene (150 mL) was added HO(CH2)2OH (10 mL, 179 mmol) and p-toluenesulfonic acid H2O (0.57 g, 3 mmol). The reaction mixture was brought to reflux and the H2O generated was removed by azeotropic distillation (using a Dean-Stark separator). The reaction mixture was then cooled and washed with a saturated NaHCO3 solution. The aqueous phase was extracted with Et2O and the combined organic layers dried over anhydrous Na2SO4. The solvent was removed in vacuo and the resulting residue purified over silica (isooctane/EtOAc, 95:5) to afford 12.1 g (95% yield) of the desired product which was characterized as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1.O[CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:48]([O:47][C:46]([NH:45][CH2:44][CH2:43][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1)=[O:52])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)OC(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.197 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 166c), 0.506 ml of tert-butyl (2-hydroxyethyl)carbamate and 0.848 g of triphenylphosphine in 10 ml of tetrahydrofuran at 0° C. is admixed dropwise with 0.66 ml of diisopropyl azodicarbonate. The reaction mixture is warmed to room temperature, stirred further for 22 hours and subsequently concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.50 (2:1 EtOAc-heptane); Rt=5.39.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[N+:14]([O-])=O)=[CH:4][CH:3]=1>CO.O.[Ni]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH2:14])=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(F)cc1)C1CCCCC1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(F)cc1)C1CCCCC1N
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To crude (4-fluoro-benzyl)-methyl-(2-nitro-cyclohexyl)-amine (1.0 mMol) in (5:1) MeOH/H2O (30 mL) was added Raney-Nickel. The reaction mixture was placed under H2 (1 atm) and stirred for 16 h. The slurry was filtered through Celite and the volatiles removed in vacuo to yield N-(4-Fluoro-benzyl)-N-methyl-cyclohexane-1,2-diamine (20 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:38]([O:40][C:41]1[CH:47]=[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]2)[C:45]([CH3:60])=[CH:44][C:42]=1[NH2:43])[CH3:39].Cl>FC(F)(F)CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:45]([CH3:60])[C:46]([N:48]4[CH2:53][CH2:52][CH:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]4)=[CH:47][C:41]=3[O:40][CH2:38][CH3:39])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 24 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (0.13 g, 0.25 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.087 g, 0.25 mmol) in 2,2,2-trifluoroethanol (1.5 mL) was added HCl (4M in dioxane) (0.13 mL, 0.50 mmol). The reaction was heated to 180° C. for 40 min in a microwave. The reaction was determined to be complete by HPLC. The reaction mixture was quenched with saturated NaHCO3 and sequentially extracted with DCM and EtOAc. The organic layer was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound (0.05 g, 0.06 mmol, 24%). 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.36 (d, J=5.9 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J=4.9 Hz, 1H), 8.09 (br. s., 1H), 7.74 (dd, J=14.1, 8.9 Hz, 2H), 7.56 (s, 1H), 7.27-7.52 (m, 3H), 7.21 (t, J=7.9 Hz, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.75 (s, 1H), 6.63 (d, J=4.8 Hz, 1H), 4.79-4.97 (m, 1H), 4.07 (q, J=6.7 Hz, 2H), 3.12-3.24 (m, 2H), 3.05 (d, J=11.1 Hz, 2H), 2.98 (s, 3H), 2.61 (t, 2H), 2.14 (s, 3H), 1.62-1.87 (m, 4H), 1.17-1.59 (m, 12H). MS (M+H, ES+) 824.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.Br[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C(O)C>[CH:15]([N:2]1[CH:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1Cc2ccccc2CC1C(=O)O
Yield: 88 %

Procedure:
A solution of 1,2,3,4-tetrahydro-3-isoquinoline-carboxylic acid (9 g, 42 mmol), 2-bromopropane (8 ml, 84 mmol) and 1N NaOH (168 mmol) in ethanol (170 ml) was refluxed for 5 hours, then 2-bromopropane (8 ml, 84 mmol) and 1N NaOH (168 ml, 168 mmol) were added and the mixture was refluxed for 5 hours. Ethanol was removed and the aqueous solution was treated with 6N hydrochloric acid to pH=7. Unreacted starting material was recovered by filtration and the solvent was removed under reduced pressure. The crude was dissolved in ethanol, the inorganics salts were filtered off and the organic solution was evaporated under reduced pressure. This procedure was repeated three times yielding 8.1 g (yield 87%) of pure N-isopropyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid which was used for the next step without further purification.