Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C(OCC)C>[CH2:1]([C:8]1[C:13]([C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[C@@H]1CN(c2ccc(C3(O)CCN(C)CC3)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a mixture of 500 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 10 ml of diethyl ether was added dropwise 1.99 ml of a 2.45 M hexane solution of n-butyllithium at −78° C. After stirring at the same temperature for 30 minutes, a solution of 552 mg of 1-methyl-4-piperidone in 3 ml of diethyl ether was added dropwise thereto. After stirring at the same temperature for 30 minutes, the temperature was elevated to room temperature. The organic layer was separated by adding water and ethyl acetate to the reaction mixture, and then it was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by NH-silica gel column chromatography with 5% methanol/ethyl acetate, to give 125 mg of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)ccc1O
Reactant: C[Si](C)(C)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCc1cc(Br)ccc1O[Si](C)(C)C
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
21.3 g (100 mmol) of 2-allyl-4-bromophenol, 12.1 g (120 mmol) of triethylamine (hereinafter referred to as “TEA”), and 120 ml of distilled tetra hydrofuran (hereinafter referred to as “THF”) were loaded into a 300-ml four-necked flask equipped with a reflux pipe with a calcium chloride dry pipe, a dropping funnel, a nitrogen gas introducing pipe, and a mechanical stirring device. The mixture was placed under nitrogen, and was stirred at 0 to 5° C. During the stirring, 11.0 g (120 mmol) of chlorotrimethylsilane were slowly added to the mixture from the dropping funnel. After the completion of the dropping, the resultant was subjected to a reaction at the temperature for 1 hour and then at room temperature for 6 hours. After that, the solvent, excessive trimethylamine, and excessive chlorotrimethylsilane were removed by condensation under reduced pressure, and the residue was washed with water and dried. Thus, 2-allyl-4-bromo-1-trimethylsiloxybenzene was quantitatively obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:12](=[N:23]OC(=O)C)[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=1)[CH3:2].N1C(C)=CC=CC=1C>C1(C)C=CC=C(C)C=1>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:12]1[C:7]2[C:8](=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH:6]=2)[NH:11][N:23]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccc(N)c(C(CCNC(=O)OC(C)(C)C)=NOC(C)=O)c1
Solvent: Cc1cccc(C)n1
Solvent: Cc1cccc(C)c1
Product: CCOC(=O)c1ccc2[nH]nc(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A solution of ethyl-4-amino-3-[3'-(N-tert-butyloxycarbonylamino)-1'-acetoxyiminopropyl]benzoate (2.8 g, 7.1 mmol) and 2,6-lutidine (0.83 ml, 7.1 mmol) in m-xylene (200 ml), was heated at reflux in Dean-Stark apparatus for 5 hours. The solution was then cooled to ambient temperature and the solvent evaporated in vacuo. The crude residue was purified by flash chromatography (eluent 1:1 petrol:ethyl acetate) to give the indazole (0.95 g, 67%) as a colourless oil. NMR (250 MHz, CDCl3) δ 1.42 (12H, m), 3.20 (2H, t, J=7 Hz), 3.65 (2H, m), 4.41 (2H, q, J=7 Hz), 5.09 (1H, br t), 7.44 (1H, d, J=9 Hz), 8.05 (1H, dd, J=9 and 2 Hz), 8.45 (1H, br s), 10.50 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4](I)[CH:3]=1.[C:17]([CH:19]1[CH2:22][CH2:21][CH2:20]1)#[CH:18]>CCN(CC)CC.C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:18]#[C:17][CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reactant: C#CC1CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C#CC1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To the solution of tert-butyl 6-chloro-4-iodopyridin-3-ylcarbamate (7.0 g, 19.8 mmol) in Et3N (100 mL) was added the solution of ethynylcyclobutane in THF (prepared in step a), Pd(PPh3)2Cl2 (1.8 g, 2.1 mmol) and CuI (400 mg, 2.1 mmol). The reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with water and extracted with dichloromethane (3×100 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether as eluant) to afford tert-butyl 6-chloro-4-(cyclobutylethynyl)pyridin-3-ylcarbamate (3.6 g, 60% yield). 1H NMR (300 MHz, CDCl3) δ: 9.11 (br, s, 1H), 7.22 (s 1H), 6.97 (s, 1H), 3.39-3.25 (m, 1H), 2.48-1.98 (m, 6H), 1.52 (s, 9H).
Reaction SMILES: B(F)(F)F.C([N:12]1[C:21](=[O:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]2[S:16][CH2:17][CH2:18][CH2:19][N:14]2[C:13]1=[O:29])C1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:23]1([C:20]2[C:21](=[O:22])[NH:12][C:13](=[O:29])[N:14]3[CH2:19][CH2:18][CH2:17][S:16][C:15]=23)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: FB(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
Boron trifluoride (0.68 ml) was added to a solution of 7-benzyl-9-phenyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (1 g) in toluene (40 ml) and was refluxed for 14 hours. Methanol (7 ml) was added to the reaction solution and the mixture was stirred for 30 minutes. The resulting solution was concentrated to dryness, and the residue was dissolved in methylene chloride and ethyl ether. The insoluble material was obtained by filtration and the product was washed by aqueous methanol. After the washing, it was recrystallized from DMF-water to give colorless crystals (0.33 g, 44%).
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1Cl)C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=3)[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:60])C1C=CC=CC=1>>[Cl:59][C:56]1[CH:57]=[CH:58][C:53]([CH2:52][CH2:51][N:48]2[CH2:47][CH2:46][N:45]([C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([F:60])[CH:41]=3)[CH2:50][CH2:49]2)=[CH:54][CH:55]=1
Reactant: Fc1cc(N2CCN(CCc3ccc(Cl)cc3)CC2)ccc1OCc1ccccc1
Agent: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Oc1ccc(N2CCN(CCc3ccc(Cl)cc3)CC2)cc1F
Yield: 87.4 %

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)-4-[2-(4-chlorophenyl)-ethyl]piperazine (373 mg), to provide crude 4-[4-[2-(4-chlorophenyl)-ethyl]piperazin-1-yl]-2-fluorophenol (257 mg).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[O:17][N:16]=[C:15]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:18]([C:15]2[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[O:17][N:16]=2)[CH3:19])=[CH:25][CH:24]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Cc1ccc(C(C)c2cc(NC(=S)NC(=O)c3ccccc3)on2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)c2cc(NC(N)=S)on2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 448.3 %

Procedure:
This thiourea (4.65 g) was dissolved in tetrahydrofuran (50 ml) and then methanol (50 ml) and potassium carbonate (3.15 g) were added, after which the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added a small amount of water, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and thereafter concentrated under reduced pressure, to obtain 3-[1-(4-isobutyl-phenyl)-ethyl]-isoxazol-5-yl-thiourea (15.52 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[Cl:11][CH2:12][NH:13][CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16]>C1C=CC=CC=1>[Cl:11][CH2:12][N:13]([CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[N:4][N:5]=1)=[O:10]
Reactant: O=C=Nc1nnc(CCl)s1
Reactant: COCC(C=O)NCCl
Solvent: c1ccccc1
Product: COCC(C=O)N(CCl)C(=O)Nc1nnc(CCl)s1

Procedure:
5-Chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-chloromethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-chloromethyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)cc2cccnc12
Yield: 32.3 %

Procedure:
A solution of 6-methoxy-8-nitro-quinoline (9 g, 44.1 mmol) in HBr (100 mL) as heated at 110° C. overnight. Additional HBr (80 mL) was added and the reaction continued to heat for an additional 24 hours. The cooled reaction mixture was basified with 2.5 N NaOH (800 mL) and extracted into EtOAc (2×300 mL). The organic fractions were combined, dried over Na2SO4 and purified by column chromatography (50% EtOAc/hexane) to afford 2.71 g (32%) of the title compound as a white solid: mp discolors above 100° C., MS(−)ESI m/z 189 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21]>>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1cc(N)ccc1-c1cccc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
This compound was made according to the General Method 14 (EXAMPLE 191) from 3-nitrobenzene boronic acid (673.2 mg, 3.82 mmol) and 4-bromo-3-methylaniline (710.2 mg, 3.82 mmol) to afford 540 mg (62%) of 4-amino-2-methyl-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-5 =R6 =R8 =H, R2 =nitro, R7 =methyl). Data for 4-amino-2-methyl-3'-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.13 (dd, J=7.5, 1.1, 1H), 8.09 (dd, J=3.9, 1.8, 1H), 7.73 (ddd, J=7.7, 1.6, 1.4, 1H), 7.66 (dd, J=8.0, 7.8, 1H), 6.99 (d, J=8.0, 1H), 6.60 (m, 1H), 4.73 (br s, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:11]1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@H:14]([Cl:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:11]1[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(CO)cc2)[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(C=O)cc2)[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
An ice cold mixture of 9-1 (43 mg, 0.089 mmol), 4 Å molecular sieves (56 mg) and NMO (16 mg, 0.14 mmol) in dichloromethane (0.5 mL) was treated with TPAP (3 mg, 0.009 mmol). The mixture was stirred for 5 min. at 0° C. and then for 1 h at room temperature. The mixture was then filtered through a pad of silica gel, washing with ethyl acetate. The solvents were evaporated and the residue was purified by flash chromatography on silica gel (10% ethyl acetate/hexanes) to give 9-2 (34 mg, 79%).
Reaction SMILES: [P:1]([F:5])([F:4])(=[O:3])[OH:2].F[P-](F)(F)(F)(F)F.[Li+:13].[Cl-].[Mg+2:15].[Cl-].C(=O)(OC)OC>>[P:1]([F:5])([F:4])([O-:3])=[O:2].[Mg+2:15].[P:1]([F:5])([F:4])([O-:3])=[O:2].[P:1]([F:5])([F:4])([O-:3])=[O:2].[Li+:13]
Reactant: O=P(O)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(=O)OC
Product: O=P([O-])(F)F
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Difluorophosphoric acid (reagent, produced by Fluorochem Ltd.) (15.4 g) was weighed into a 250 ml-volume PFA vessel, and 3.4 g of lithium hexafluorophosphate (reagent, produced by Stella Chemifa Corporation) was added. Furthermore, 7.1 g of magnesium chloride (reagent, produced by Wako Pure Chemical Industries, Ltd.) and 15.0 g of dimethyl carbonate (reagent, produced by Kishida Chemical Co., Ltd.) were added, and the mixture was stirred for 1 hour under nitrogen flow and after heating at 130° C. for 17 hours, cooled to room temperature to obtain a mixed crystal of magnesium difluorophosphate and lithium difluorophosphate. Anion analysis was performed in the same manner as in Example 2-6, as a result, the obtained difluorophosphate ion was 91% in terms of the relative area.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:27](=[CH:28][CH:29]=1)[O:26][CH2:25][C:21]1([CH2:24][O:23][CH2:22]1)[C:9]12[CH2:13][O:12][C:11]([N:14]([C:18]([O-:20])=[O:19])[C:15]([O-:17])=[O:16])=[N:10]1>[Pd].CCO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:27](=[CH:28][CH:29]=1)[O:26][CH2:25][C:21]1([CH2:24][O:23][CH2:22]1)[C:9]12[CH2:13][O:12][C:11]([N:14]([C:18]([O:20][C:9]([CH3:21])([CH3:13])[CH3:8])=[O:19])[C:15]([O:17][C:6]([CH3:7])([CH3:29])[CH3:5])=[O:16])=[N:10]1
Reactant: COCC#Cc1ccc2c(c1)C1(COC(N(C(=O)[O-])C(=O)[O-])=N1)C1(COC1)CO2
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Yield: 199.7 %

Procedure:
[6′-(3-methoxyprop-1-yn-1-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg, 0.067 mmol) and 10% palladium on carbon (7 mg) in EtOH (1.4 mL) was stirred for 13 hours under a hydrogen atmosphere (4.5 kgf/cm2). The mixture was filtered off, and the filtrate was evaporated to give crude di-tert-butyl [6′-(3-methoxypropyl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C(Cl)(Cl)(Cl)Cl.[OH-:19].[Na+].Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.CCOC(C)=O>[OH:19][C:2]([CH3:13])([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: [OH-]
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)C(C)(C)O)cc1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-1-(4-(methylthio)phenyl)propan-1-one (28.5 g, 147 mmol, Step 1), Aliquat 336 (11.0 mL, 24 mmol) and carbon tetrachloride (21 mL, 218 mmol) in toluene (43 mL) was added sodium hydroxide (12.9 g, pellets, 322 mmol). The reaction was stirred at 15° C. for 2 h and then at r.t. for 16 h. The reaction was diluted with water (100 mL), brine (100 mL) and EtOAc (300 mL). The aqueous phase was acidified with 1N HCl and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with 15% EtOAc in hexane to give the title compound as a thick syrup.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:37][NH2:38]>CO>[CH3:37][NH:38][CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1
Reactant: CN
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CO
Product: CNCc1cc2ncn(-c3cc(O[C@H](C)c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1

Procedure:
A solution of 75 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.32 ml methylamine (2 M solution in methanol) in 1.5 ml methanol is stirred in a microwave vial at 120° C. for 6 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:17](N)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.N([O-])=O.[Na+].[OH-].[Na+].[ClH:25]>[Cu]Cl>[Cl:25][C:17]1[C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ncccc2N)CC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)[C@H]1CC[C@H](c2ncccc2Cl)CC1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
To a solution of cis/trans-4-(3-amino-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:11) (0.570 g, 2.30 mmol) in concentrated hydrochloric acid (37%; 20 ml) was added sodium nitrite (0.292 g, 4.23 mmol) in small portions at 0-5° C. Stirring for 20 minutes was followed by addition of copper (I) chloride (0.493 g, 4.83 mmol) in one portion. After 10 minutes the reaction mixture was heated to 65° C. (oil bath temperature). The temperature was maintained at 65° C. for 20 h. The reaction mixture was cooled to 0-5° C. and adjusted to pH 4 by addition of aqueous sodium hydroxide solution (32%; 20 ml). The green aqueous layer was extracted with three 75 ml-portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography over SiO2 with n-heptane/ethyl acetate as eluent to give the title compound (0.424 g, 77%) as off-white solid. MS m/e: 240 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][CH2:17][C:16]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:18][O:15][CH2:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCO1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCN(C2COC2)CC1
Reaction time: 1.25 h
Yield: 66.3 %

Procedure:
To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (200 mg, 1.0 mmol) in DCE (6 mL) was added oxetanone (60 mg, 0.83 mmol) in DCE (2 mL). After 75 min, sodium triacetoxyborohydride (282 mg, 1.33 mmol) was added in one portion. After 20 hours at ambient temperature, the reaction mixture was loaded directly onto a 5 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo followed by flash chromatography of the resultant residue (silica, 5 g column, Si-SPE, 0-10% methanol in dichloromethane) afforded the title compound as a white solid (141 mg, 67%). 1H NMR (300 MHz, CDCl3): 4.62-4.61 (m, 4H), 4.44 (s, 1H), 3.46-3.45 (m, 2H), 2.67 (d, J=10.9 Hz, 2H), 2.02-1.88 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][CH2:21][C:22]([CH2:26][F:27])([OH:25])[C:23]#[CH:24]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([CH2:26][F:27])([OH:25])[CH2:21][F:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(O)(CF)CF
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC(O)(CF)CF)c(F)cc1OCC2
Yield: 18 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol to give the titled compound as a brown solid (42 mg, 18%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([O:21][C:22](=[O:49])[N:23]([C@H:36]1[CH2:40][CH2:39][C@@H:38]([C:41]2[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=2)[CH2:37]1)[C@@H:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:25])([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[CH:47]/[C:44]1[CH:45]=[CH:46][C:41]([C@@H:38]2[CH2:39][CH2:40][C@H:36]([N:23]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:49])[C@@H:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH2:37]2)=[CH:42][CH:43]=1)[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](c2ccc(C=O)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc([C@@H]2CC[C@H](N(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
Under a nitrogen stream, sodium hydride (60% in mineral-oil dispersion) (44 mg, 1.1 mmol) was suspended in tetrahydrofuran (5 mL), followed by addition of ethyl diethylphosphonoacetate (0.24 mL, 1.2 mmol), and the mixture was stirred for 10 minutes at room temperature. A tetrahydrofuran solution of [(1S,3R)-3-(4-formylphenyl)cyclopentyl][(1R)-1-(naphthalen-1-yl)ethyl]carbamic acid tert-butyl ester (407 mg, 0.92 mmol) was added to the mixture, and the mixture was stirred further for 1 hour at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the solution was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane: 10/90-15/85) to give the title compound (475 mg).