Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:36](=[O:37])[CH2:35][C:34]([CH3:39])([CH3:38])[CH2:33][C:32]2=[O:40])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[OH:51])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:52]1[CH:57]=[CH:56][CH2:55][CH2:54][CH2:53]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:32](=[O:40])[CH2:33][C:34]([CH3:39])([CH3:38])[CH2:35][C:36]2=[O:37])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[O:51][CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][O:52]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OC2CCCCO2)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Yield: 85 %

Procedure:
A mixture of methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β- D-glucopyranoside (500 mg, 0.6 mmol), 3,4-dihydro-2H-pyran (5 mL) and -p-toluenesulphonic acid (5 mg) in dry acetonitrile (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 7 with the addition of triethylamine and then evaporated to dryness. The residue was taken up in dichloromethane (30 mL), washed with water (2×10 mL) and the organic phase dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOA 2:1 as the mobile phase to give methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-4-O-tetrahydropyranyl-1-thio-β-D-glucopyranoside (5) (420 mg, 85%).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[O-:16][P:17]([O-])([O-])=O.[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].S(=O)(=O)(O)O>>[O:5]=[P:1]12[O:4][P:7]3([O:10][P:12]([O:15][P:17]([O:9]3)([O:3]1)=[O:16])(=[O:13])[O:2]2)=[O:8]
Reactant: O=P(O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Yield: 35 %

Procedure:
The conventional methods for the production of wet process phosphoric acid, finely ground phosphate rock is reacted with dilute phosphoric acid (10% P2O5 to 25% P2O5) and sulphuric acid which may or may not be diluted. The reaction product is leached (i.e., digested or reacted with the acid) to yield a crude aqueous phosphoric acid solution in which is suspended a substantial quantity of solid impurities. This slurry is filtered to separate most of the undissolved gypsum and other solid impurities to yield a crude (22% P2O5 to 35% P2O5) aqueous product sometimes known as the number one filtrate. This filtrate contains suspended, finely divided, impurities that were not removed during the solidliquid separation step plus solids that have crystallized after filtration. The solution also contains dissolved impurities. Reference is made to Chapter 16 of Volume II, Phosphorus and its Compounds, Van Wazer, Interscience Publishers (1961).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].CCCCCCC>C(O)(C)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:24][C@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Br)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc(-c2ccn(C[C@@H](C)c3ccccc3)n2)sc1C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide and 2-(bromo-1-methyl-ethyl)-benzene as described in Example 90 and isolated by chiral separation (90:10, heptane:isopropyl alcohol). 1H NMR (400 MHz, CDCl3) δ 7.20-7.39 (m, 8H), 7.13 (d, J=4 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.68 (d, J=2 Hz, 1H), 5.98-6.04 (bm, 1H), 4.62 (d, J=8 Hz, 2H), 4.17-4.32 (m, 2H), 3.33-3.44 (m, 1H), 2.75 (s, 3H), 1.29 (d, J=4 Hz, 3H); MS (M+H)+=417.2; Rt=1.32 min; HRMS (M+H)+=417.17.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:7][C:5]1([F:8])[CH2:4][C@H:3]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)[C@@H:2]([NH:1][C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][N:25]=2)[CH2:6]1
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.15 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 29 mg, 0.16 mmol) and DIPEA (26 μl, 0.15 mmol) in dry DMSO (485 μl). The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(C=Cc3ccccc32)CC1
Yield: 102 %

Procedure:
In the same manner as in Example 22, step 4 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.091 g, 0.242 mmol) obtained in Example 22, step 3 and spiro[inden-1,4′-piperidine]hydrochloride (WO2004/028459, 0.059 g, 0.267 mmol), the title compound (0.127 g, 95%) was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.CC(O)C>CS(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[C:21]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Nc2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)no1
Temperature: 120 °C

Procedure:
To a slurry of (5-t-butyl-isoxazol-3-yl)-(2-chloro-pyrimidin-4-yl)-amine (Example 2, Step A) (0.120 mg, 0.47 mmol) in DMSO (0.120 mL) was added 3-aminobenzenesulfonamide (0.082 g, 0.47 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 1 h at which time TLC indicated the disappearance of starting material. IPA (5 mL) was added and the mixture was filtered and washed with IPA (2×1 mL) to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[CH2:12]([NH:19][C:5]1[N:4]([CH3:11])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: O
Product: Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 80.6 %

Procedure:
2 g (7.02 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 11 g (0.1 mole) of benzylamine in 50 ml ethanol for 10 hours at boiling temperature. After cooling, the reaction mixture is poured on 100 ml water, the separated product is filtered and washed with water (20 ml). After vacuum drying, 1.76 g (81 percent of theory) of 5-benzylamino-3-bromo-1-methyl-4-nitropyrazole are obtained in the form of yellow needles with a melting point of 133° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:12]([C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([Br:8])[CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, into a cold (10° C.) solution of trifluoroacetic acid (240 mL) was added a solution of 3-bromobenzophenone (11 g, 42.1 mmol) in CH2Cl2 (120 mL) over 10 minutes, followed by slow addition of NaBH4-pellets (19 g) over 1 hour. The reaction mixture was stirred at room temperature for 18 h, poured into ice, basified with NaOH (50%) to pH 8 and extracted with ether. The organic extracts were combined, dried over MgSO4, treated with charcoal and filtered. The filtrate was concentrated in vacuo to give 1-benzyl-3-bromobenzene as an oil (9.65 g, 92% yield) MS m/e (M+H)+ 248; 1H NMR (400 MHZ, DMSOd6) δ 3.89 (s, 2H,), 7.19-7.39 (m, 9H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=441.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-4,6-bis-trifluoromethyl-benzoic acid (CAS 896120-49-3).
Reaction SMILES: [CH2:1]([C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].[CH3:16]OC(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:14][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])([CH3:15])[C:13]2[C:8]([CH2:7][CH:6]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: C=CCC1(C)C(=O)CCc2ccccc21
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C=CCC1(C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of Example 123A (10.1 g, 50.5 mmol), trimethylorthoformate (20 mL), p-toluenesulfonic acid monohydrate (60 mg, 0.315 mmol) in methanol (100 mL) was heated at 60 C for 2 hours. After cooling to room temperature, the solution was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with hexane to provide the title compound as a colorless oil (7.8 g, 73%). 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 3 H), 2.44 (dd, J=13.8, 7.4 Hz, 1H), 2.65 (dd, J=13.6, 7.0 Hz, 1 H), 3.41 (d, J=3.7 Hz, 2 H), 3.54 (s, 3 H), 4.75 m, 2 H), 4.90 (t, J=3.7 Hz, 1 H), 5.24 m, 1 H), 7.10 m, 2 H), 7.19 m, 1 H), 7.40 (d, J=7.8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)cc1
Reaction time: 24 h
Yield: 84 %

Procedure:
A mixture of 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (ButtPark Ltd, 2.86 g, 14.55 mmol), 4-(methylthio)phenylboronic acid (Aldrich, 2.83 g, 1.1 eq), tetrakistriphenylphosphine palladium (0) (0.2 g) and sodium carbonate (4.04 g, 2.6 eq) in DME (200 ml) and water (100 ml) was heated under reflux with stirring under N2 for 24 h. The reaction mixture was concentrated in vacuo and the resultant mixture partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated in vacuo to a purple solid. Purification by flash column chromatography with cyclohexane:ethyl acetate as (6:1) as eluant gave the title compound as a yellow crystalline solid (3.869, 84%).
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[CH:14]=[C:15]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:16]=[N:17][C:18]=1[Cl:19]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:27]2[C:28]([Cl:30])=[C:29]3[C:24]([C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21][N:20]3[C:15]3[CH:16]=[N:17][C:18]([Cl:19])=[C:13]([NH2:12])[CH:14]=3)=[CH:25][C:26]=2[F:32])[CH2:9]1
Reactant: NC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)cnc1Cl
Yield: 49.6 %

Procedure:
To dimethylsulfoxide solution 1 ml of 53 mg of 3-aminoazetidine dihydrochloride and 146 mg of triethylamine at 80° C. was added 80 mg of 1-(5-amino-6-chloropyridine-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, aisd the solid content was collected by filtration, washed with ethanol, and dried to obtain 45 mg of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[F:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]2)=[CH:15][CH:14]=1>>[CH3:29][N:28]([CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:31][CH:30]=2)[CH2:27][CH2:26]1)[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: CNC1CCN(CCCCOc2ccc(F)cc2)CC1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCCCOc2ccc(F)cc2)CC1

Procedure:
The condensation of 2 g (14.8 mmol) of phenyl isothiocyanate with 5.25 g (14.8 mmol) of 1-[4-(4-fluorophenoxy)butyl]-4-methylaminopiperidine dihydrochloride (cf. WO 97/05134) according to the protocol of Example 1.1 provides 5.5 g (Yd: 90%) of white crystals of formula 7.1:
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([F:13])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)c(F)cc1N
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(N)cc1F
Reaction time: 0.5 h

Procedure:
To an amount of 4-amino-2-fluoro-5-methoxybenzoic acid (4 g, 21.62 mmole) that was dissolved in DCM (40 ml) and MeOH (11 mL), was added TMS-diazomethane (16.2 mL, 32.43 mmole) slowly. The mixture was stirred at r.t for 30 mins. After the removal of solvent, the resulting tan solid (4.0 g, 93%) carried onto the next reaction without any purification. [M+H] calc'd for C9H10FNO3, 200; found 200.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CC(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=2[C:9](=[O:11])[CH3:10])[CH2:22][CH2:21]1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC1CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(2,6-dihydroxyphenyl)ethanone (50.0 g, 328 mmol) in acetone (1000 mL) was added potassium carbonate (227 g, 1643 mmol) and (bromomethyl)cyclopropane (35.1 mL, 361 mmol). The mixture was stirred at 50° C. for 2 days. The reaction mixture was filtrated on Celite®, and then the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in hexane. Then the suspension was stirred at 80° C. for 30 min. The solution was filtered and the filtrate was allowed to cool to room temperature. The resulting white solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 1-{2-[(cyclopropylmethyl)oxy]-6-hydroxyphenyl}ethanone as a pale yellow solid (56.3 g, yield; 83%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 150 °C
Reaction time: 4 h

Procedure:
128 g naphthalene (1.0 m) and 160 g sulfuric acid 98% (1.6 m) were charged to a reactor and mixed. This mixture was heated rapidly to 150° C. and agitated at 150° C. for 4 hours to obtain a naphthalenesulfonic acid having an acid value of 408.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:20]1[O:21][CH:15]([C:14]2[CH:17]=[CH:18][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)=[CH:12][CH:13]=2)[O:16][CH2:19]1
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3OCCO3)cc2)nc1

Procedure:
To a solution of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde (5.00 g, 20.5 mmol) in benzene (100 mL) were added ethylene glycol (2.28 mL, 41.0 mmol) and p-toluenesulfonic acid (0.50 g), and the resulting solution was heated to reflux for 3 hours while removing water with a Dean-Stark. The reaction solution was washed with a saturated sodium bicarbonate solution, and subsequently washed with brine. The benzene layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 5.88 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: ICC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (200 mg) in DMF (5 mL) were added potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg), and the mixture was stirred at room temperature for 15 hr. Potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[C:34](C1C=CC(F)=C([C@]23CO[C@@H](C4ON=C(C)C=4)C[C@H]2CSC(NC(=O)C2C=CC=CC=2)=N3)C=1)#[N:35]>>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Reactant: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)n1
Product: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)n1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C40) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C37) in Example 10. The product was obtained as a white solid. Yield: 227 mg, 126%. LCMS m/z 477.2 [M+H+]. 1H NMR (400 MHz, CD3OH) δ 8.09 (br s, 2H), 7.83-7.86 (m, 2H), 7.61 (q, J=2.3 Hz, 1H), 7.55-7.65 (m, 2H), 7.40-7.51 (m, 3H), 4.91 (dd, J=11.8, 2.4 Hz, 1H), 4.35 (dd, J=11.9, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=13.1, 3.7 Hz, 1H), 2.82 (dd, J=13.2, 2.8 Hz, 1H), 2.38-2.47 (m, 1H), 2.15 and 2.01 (d, J=3.8 Hz, 3H), 2.03-2.07 (m, 1H).
Reaction SMILES: [NH3:1].CO.C([O:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:17]=2)[N:10]=1)=O)C>CO>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:17]=2)[N:10]=[C:9]([C:7]([NH2:1])=[O:6])[CH:14]=1
Reactant: CCOC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Reaction time: 3 h

Procedure:
In a 50-ml vial with a screw-top septum, 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid ethyl ester (0.445 g) was dissolved in 3 ml methanol. 7N NH3/MeOH (6 ml) was added to the solution and stirred for 3 hours, at which time the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was suspended in about 3 ml methanol. The suspension was collected by vacuum filtration and washed with cold methanol to provide 0.267 g of 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid amide as a very pure yellow solid (65% yield).