Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:16])[C:13](O)=[O:14])[S:8][CH:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].OC(C(F)(F)F)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:16])[C:13]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][C:37]3=[O:46])[CH2:34][CH2:35]2)=[O:14])[S:8][CH:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(C)CCN1C(=O)C(C(C)C(=O)O)SC1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCN1C(=O)C(C(C)C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)propanoic acid (11 mg, 0.034 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one TFA (17 mg, 0.051 mmol) and DiPEA (24 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (17 mg, 0.044 mmol) and the reaction mixture was stirred at RT for 16 hours. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A mixture of A mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (264 mg), HOBt (290 mg) and EDCI (334 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1C(NCC1CCCCN1)=O.BrC1C=CC(Br)=CC=1.FC(F)(F)CO>>[F:1][C:2]([F:27])([F:28])[CH2:3][O:4][C:5]1[CH:6]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=1
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: Brc1ccc(Br)cc1
Solvent: OCC(F)(F)F
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1

Procedure:
In another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is then treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Subsequently, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpyridine, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide. Finally, the 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide is treated with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:16][C:17](=[O:19])[CH3:18])([CH3:15])[CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH2:20]([C@@]1(CCC2N(C)C=CC=2)COC(=O)N1)C>>[C:1]([O:4][CH2:5][C@@:6]([NH:16][C:17](=[O:19])[CH3:18])([CH2:15][CH3:20])[CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC[C@@]1(CCc2cccn2C)COC(=O)N1
Reactant: CC(=O)N[C@](C)(CCc1cccn1C)COC(C)=O
Product: CC[C@@](CCc1cccn1C)(COC(C)=O)NC(C)=O
Yield: 77 %

Procedure:
The reaction was carried out in the similar manner to Reference example 1 (1 g) and (1h) using (4R)-4-ethyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one obtained Reference example 2 (2e) as a starting material to obtain the title compound (yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([OH:24])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.ON1C2C=CC=CC=2N=N1.Cl.[CH2:36]([N:38]=[C:39]=NCCCN(C)C)C.CN>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([N:38]([CH3:39])[CH3:36])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a suspension of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylic acid (430 mg, 1.18 mmol) in N,N-dimethylformamide (8.0 mL) were added 1-hydroxy-1H-benzotriazole (235 mg, 1.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.30 mmol), and methylamine (2.0 M solution in tetrahydrofuran, 1.20 mL, 2.40 mmol). The mixture was stirred at room temperature for 15 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-85% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (305 mg, 0.783 mmol, 66%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.O>CS(C)=O>[CH3:12][O:13][CH2:14][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: COCCl
Reactant: N#CCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11.8 g. (0.1 mole) of 2-pyridylacetonitrile in dry dimethylsulfoxide at 10° C. is added 0.1 mole of sodium hydride (dispersed in mineral oil). After 20 minutes, 0.1 mole of chloromethyl methyl ether is added with cooling and the mixture is kept at 10° C. for 2 hours, then allowed to warm to room temperature overnight. The reaction mixture is poured into water and extracted with ether. The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum and distilled to give 3-methoxy-2-(2-pyridyl)propionitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][N:18]=1.[H-].[Na+]>CN1CCCC1=O>[CH:24]1([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:6][CH:7]=3)=[N:18][CH:19]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: Clc1ccc(OC2CCCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1
Temperature: 240 °C

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (104.9 mg, 0.51 mmol), 2-chloro-5-cyclopentyloxypyridine (100 mg, 0.51 mmol) and sodium hydride (50% in oil) (26 mg, 0.54 mmol) were treated at 230° C. in 5 ml of N-methylpyrrolidinone in a microwave reactor for 1 h. Addition of a further 26 mg of sodium hydride was followed by again heating at 240° C. for 1 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 16 mg (9%), M+H+: 369.17.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][O:7][CH3:8].[F:9][C:10]([F:22])([F:21])[C:11]([NH:13][CH:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])=[O:12]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[F:9][C:10]([F:21])([F:22])[C:11]([NH:13][CH:14]1[CH2:15][C:16]2[C:19](=[CH:20][C:5]([CH2:6][O:7][CH3:8])=[C:4]([CH2:3][O:2][CH3:1])[CH:17]=2)[CH2:18]1)=[O:12]
Reactant: COCC#CCOC
Reactant: C#CCC(CC#C)NC(=O)C(F)(F)F
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COCc1cc2c(cc1COC)CC(NC(=O)C(F)(F)F)C2
Temperature: 80 °C

Procedure:
According to the procedure of Magnus et. al (Tetrahed. Lett., 34, 23-26 (1993)) a solution of commercially available 1,4-dimethoxy-2-butyne (1.32 g, 11.5 mmol) in nitrogen-degassed ethanol is heated to 80° C. with stirring under a nitrogen atmosphere. Tris(triphenylphosphine)rhodium chloride (64 mg, 0.07 mmol) and a solution of 2,2,2-trifluoro-N-[1-(2-propynyl)-3-butynyl]-acetamide (470 mg, 2.32 mmol; prepared from literature procedure; Romero, Arthur G.; Leiby, Jeffrey A PCT Int. Appl. WO 9623760) in nitrogen-degassed ethanol (2 ml) are added in portions over 2 hours. The mixture is stirred under nitrogen at 80° C. for a further 3 hours. The solvent is removed under vacuo and the residue is purified by flash chromatography on silica gel, elating with hexane/ethyl acetate (2:1)
Reaction SMILES: [C:1]1([C:7]2([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[C:22]=[S:23]>ClCCl>[CH2:17]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH2:12][N:13]([C:22](=[S:23])[NH:21][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)[CH:18]([CH3:20])[CH3:19]
Reactant: S=C=NCCN1CCCCC1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=S)NCCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A mixture of 3-phenyl-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.18 mmol) and 1-(isothiocyanatoethyl)piperidine (45.7 mg, 0.28 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (52 mg, 64.0%). 1H NMR (300 Hz, CDCl3) δ 0.87 (t, J=6.0, 3H), 0.96 (t, d=6.0, 3H), 1.40-1.63 (m, 6H), 1.63-1.75 (m, 1H), 1.78-1.90 (m, 1H), 2.30-2.60 (m, 10H), 2.58-2.70 (m, 3H), 3.83-3.95 (m, 1H), 4.26 (d, J=18.0, 1H), 5.17 (d, J=18.0, 1H), 7.02 (br s, 1H), 7.26-7.40 (m, 5H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:25](Cl)(Cl)=[O:26]>C(Cl)Cl>[C:12]([C@H:9]1[CH2:10][O:11][S:25](=[O:26])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[C@@H](CO)NCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (5.77 g, 27.8 mmol) in dry DCM (100 mL) was cooled down to −20° C., DIEA (19.39 ml, 111 mmol) was added, followed by thionyl chloride (2.228 ml, 30.6 mmol) in DCM (10 mL). The reaction mixture was stirred for 1 h at this temperature, then concentrated. The residue was purified by column chromatography to give the title compound (6.26 g) as a diastereomeric mixture. LCMS m/z=254.0 [M+H]+.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[CH:65][C:64]=1[O:72][CH3:73].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([OH:44])[CH:45]2[CH2:50][CH2:49][CH2:48][N:47]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[CH:65][C:64]=3[O:72][CH3:73])[CH2:46]2)=[CH:39][CH:38]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCCNC1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)C1
Yield: 78.5 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(4-fluorophenyl)]-3-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 4.0 g (78%) of the title compound as an off-white solid, mp 100°-105° C. (2-propanol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1.COC(OC)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C@@H:9]([C@H:10]1[CH2:11][O:12][C:16]([CH3:21])([CH3:17])[O:13]1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: C[C@@H](OCc1ccccc1)[C@H]1COC(C)(C)O1
Reaction time: 2.5 h

Procedure:
A stirred solution of (2R,3R)-3-(benzyloxy)butane-1,2-diol (the product of step ii) (0.68 g), p-toluene sulfonic acid monohydrate (34 mg) and 2,2-dimethoxypropane (0.43 mL) in toluene (10 mL) was heated to reflux for 30 min, then anhydrous sodium sulfate was added and reflux continued for 2.5 h. The reaction mixture was allowed to cool and diluted with EtOAc and saturated aqueous sodium bicarbonate and the layers separated. The organic extract was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:9 to 1:1 gradient) as eluent to give the subtitle compound as a colourless liquid. Yield: 0.46 g.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[F:15]C1C=CC(C(O)=O)=C([N+]([O-])=O)C=1>>[F:15][C:3]1[CH:2]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: CNC(=O)c1ccc(F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the procedure from 5-fluoro-N-methyl-2-nitrobenzamide (Compound 102B) with the commercially available 4-fluoro-2-nitrobenzoic acid. 1H NMR (CDCl3, 400 MHz): δ=3.04 (d, J=4.80 Hz, 3 H), 5.88 (br. s., 1 H), 7.39 (ddd, J=8.46, 7.45, 2.53 Hz, 1 H), 7.55 (dd, J=8.59, 5.31 Hz, 1 H), 7.78 (dd, J=8.34, 2.53 Hz, 1 H). MS (ES+): m/z 199.05 [MH+] (TOF, polar).
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][O:12][CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](Cl)=[O:30])[C:26]([C:32](F)([F:34])[F:33])=[N:25]1>ClCCl>[I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([O:12][CH3:13])[C:29]([C:27]3[C:26]([CH:32]([F:34])[F:33])=[N:25][N:24]([CH3:23])[CH:28]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: CONC1CCCCc2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1CCCCc2ccc(I)cc21
Temperature: 24 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of N-(3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (77 mg; 0.24 mmol), prepared as described in example P3c and triethylamine (0.037 ml; 0.26 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (47 mg; 0.24 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. The mixture diluted with dichloromethane (10 ml), washed with 1M sodium hydroxide (1 ml), 1M hydrochloric acid (1 ml) and brine (1 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude (190 mg) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.101 g (88% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as a yellow solid oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26](=[O:28])[CH3:27])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(N3CCc4cc(N)ccc43)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCc4cc(NC(C)=O)ccc43)c2cc1OC
Temperature: 20 °C
Reaction time: 7.5 h
Yield: 46 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-5-ylamine (102 mg, 0.316 mmol; free-base from Example 83) and 4-(N,N-dimethylamino)pyridine (51.2 mg, 0.42 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (88 μL, 0.93 mmol). The mixture was stirred at 20° C. for 7.5 hours, quenched with H=O (5 mL), stirred 30 min. and diluted with CHCl3 (15 mL). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (3.5% MeOH/CHCl3) afforded 53 mg of product. (M.P. >250° C. (dec); LC-MS: 365 (MH+); anal. RP18-HPLC RT: 2.79 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:22](=[O:29])[CH:23]=[C:24]([OH:28])[C:25]([OH:27])=[O:26].[Li+].[OH-]>CO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:22](=[O:29])[CH:23]=[C:24]([OH:28])[C:25]([OH:27])=[O:26])=[CH:6]2)=[CH:17][CH:16]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2cc(C(=O)C=C(O)C(=O)O)c3cc(Cl)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
To a solution of 82 mg (0.2 mmol) of 4-[5-chloro-1-(4-methoxycarbonylbenzyl)indol-3-yl]-2-hydroxy-4-oxo-2-butenoic acid, prepared in a manner similar to that described in Example 23, in 75% MeOH (35 ml) was added 42 mg (1.0 mmol) of LiOH. After the mixture was stirred for 5 hours at room temperature, the solvent was removed under reduced pressure. The residue was acidified with 1 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was evaporated and the residue was recrystallized from ethyl acetate/ether to give 63 mg of the titled compound. Yield: 79%.
Reaction SMILES: OCCCN1CC[CH:8]([C:11]2[CH:12]=[C:13]([C:17](C)(C)[C:18](N)=[O:19])C=CC=2)CC1.ClCCCO.[CH3:28][CH:29]([CH3:45])[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:34]=1)=[O:31]>>[OH:19][CH2:18][CH2:17][CH2:13][CH2:12][CH2:11][CH2:8][N:42]1[CH2:43][CH2:44][CH:39]([C:35]2[CH:34]=[C:33]([NH:32][C:30](=[O:31])[CH:29]([CH3:45])[CH3:28])[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: CC(C)(C(N)=O)c1cccc(C2CCN(CCCO)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: OCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1

Procedure:
N-({3-[1-(3-HYDROXYPROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 3-chloro-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 305.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.O.O.[Sn](Cl)[Cl:22]>C(O)C.Cl>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[C:14]([NH2:15])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: N#Cc1ccsc1Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2sccc21
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Suspend 2-(5-fluoro-2-nitro-phenylamino)-thiophene-3-carbonitrile (3.89 g, 14.78 mmol) in ethanol (40.0 ml). Dissolve tin(II) chloride dihydrate (10.00 g, 44.33 mmol) in 5N HCl (40.0 ml) and then add it to the suspension. Heat the reaction at reflux for 2.5 hours and then cool it to ambient temperature. Collect the resulting precipitate by vacuum filtration and then dry it under vacuum to give 3.32 g (83%) of the title compound: mass spectrum (ion spray): m/z=234.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][OH:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:29][CH2:30][OH:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Yield: 45.9 %

Procedure:
A mixture of 2 g (0.0076 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-caboxylate and 1.85 g (2×0.0076 mol) of potassium carbonate in 20 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 3.35 g (4×0.0076 mol) of ethylene bromohydrin are added, the mixture is heated at 80°-90° C. for 10 hours, active carbon is added, the mixture is filtered hot, the filtrate is evaporated to dryness, water is added and the precipitate formed is filtered off and washed with water. It is recrystallized from dimethylformamide to give 1.2 g of a solid melting at 237°-239° C.