Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19].COCCO>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Solvent: O
Solvent: COCCO
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A mixture comprising 10 g of the obtained 5-nitro-1,4-naphthoquinone, 3.3 g of 1,3-butadiene and 40 ml of ethylene glycol monomethyl ether was retained in a 100-milliliter autoclave at 50° C. for 6 hours with stirring. The reaction pressure was initially 1.2 atmospheres and 1.0 atmosphere when the reaction was over. Thereafter, 60 ml of water was added to the reaction mixture and cooled to 25° C. The precipitated crystals were filtered, washed with 30 ml of methyl alcohol and dried under reduced pressure to obtain 11.9 g of white 5-nitro-1,4,4a,9a-tetrahydroanthraquinone having a purity of 98%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[N:16]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]34[NH:43][CH2:42][CH2:41][N:32]3[C:33](=[O:40])[C:34]3[N:35]([CH:37]=[CH:38][CH:39]=3)[CH2:36]4)=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH3:7][C:8]1[C:12]([C:13]([N:43]2[C:31]3([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)=[CH:26][CH:27]=4)[CH2:36][N:35]4[CH:37]=[CH:38][CH:39]=[C:34]4[C:33](=[O:40])[N:32]3[CH2:41][CH2:42]2)=[O:15])=[CH:11][O:10][N:9]=1
Reactant: Cc1nocc1C(=O)O
Reactant: O=C1c2cccn2CC2(c3ccc(OCCN4CCOCC4)cc3)NCCN12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To generate the acid chloride, oxalyl chloride (0.1 mL, 1.2 mmol) and DMF (1 drop) were added to 3-methyl-1,2-oxazole-4-carboxylic acid (30 mg, 0.24 mmol) in CH2Cl2 (0.5 mL) at 0° C. The suspension was allowed to stir 15 minutes at 0° C. followed by 1 hour at room temperature. The resulting solution was concentrated to give an oil that was further dried under nitrogen. To a chilled suspension of the acid chloride (generated as above, 0.24 mmol) in pyridine (0.5 mL) was added 10a-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (20 mg, 75% pure, 0.039 mmol) in pyridine (0.3 mL). The reaction mixture was stirred at 0° C. and then at room temperature. After 2.5 hours an additional batch of acid chloride (0.24 mmol) was prepared as above, diluted in pyridine (0.3 mL) and added to the reaction mixture. The mixture was stirred overnight at room temperature. Water (2 mL) was then added and the mixture extracted with dichloromethane (3×1.5 mL). The organic layers were dried (MgSO4), filtrated and concentrated in vacuo to give a residue that was purified by preparative LCMS (reverse phase, acetonitrile-water containing 0.1% formic acid) to give 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (110) (7 mg, yield 36%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:31]([C:33]([CH3:37])([CH3:36])[C:34]#[CH:35])[CH3:32])[CH:29]=[CH2:30]>>[CH2:28]([N:31]([C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH3:32])[CH:29]=[CH2:30]
Reactant: C#CC(C)(C)N(C)CC=C
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: C=CCN(C)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and Allyl-(1,1-dimethyl-prop-2-ynyl)-methyl-amine were converted to yield Allyl-{1,1-dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amine as brown oil, MS: 415 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.N[C:14]1C=CC(C)=CC=1.C(OC=C(C(OCC)=O)C(OCC)=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2nccc(Cl)c2c1
Reactant: Cc1ccc(N)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Product: Cc1ccc2nccc(Cl)c2c1

Procedure:
This compound was made in a manner analogous to that of the synthesis of 4-chloro-6-fluoroquinoline described in Example 12. Starting from p-toluidine and diethyl ethoxymethylenemalonate the compound was obtained as a solid of mp 47°-51°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])[CH2:21][CH2:20]3)=[C:15]([O:31][CH3:32])[CH:14]=1)[CH2:6][CH2:5]2.CS([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>>[OH:30][C:27]([CH3:28])([CH3:29])[CH2:26][N:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:16]2[CH:17]=[CH:18][C:13]([N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@H:38]5[CH2:42][CH2:41][CH2:40][O:39]5)[CH:3]=4)[C:8]3=[O:12])=[CH:14][C:15]=2[O:31][CH3:32])[CH2:20][CH2:21]1
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1
Reactant: CS(=O)(=O)C[C@H]1CCCO1
Product: COc1cc(N2CCc3cc(OC[C@H]4CCCO4)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
6-Hydroxy-2-{4-[4-(2-hydroxy-2-methyl-propyl)-[1,4]diazepan-1-yl]-3-methoxy-phenyl}-3,4-dihydro-2H-isoquinolin-1-one and (R)-2-methanesulfonylmethyl-tetrahydrofuran were reacted according to Method K1. In this way the product was obtained with molecular weight 523.68 (C30H41N3O5); MS (ESI): 524 (M+H+).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:23]C(C)([O-])C.[K+].CI>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:23])[CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a solution of Boc-D-Trp-OH (15.0 g) in DMF (150 ml) were added potassium tert-butoxide (13.8 g) and methyl iodide (10.5 g) under ice-cooling. After stirring under ice-cooling for 30 minutes and at room temperature for 15 minutes, the reaction mixture was poured into ice-cooled 0.24 NHCl, followed by extraction with ethyl acetate. The extract was washed with 5% NaHSO3 and saturated aqueous sodium chloride. Removal of the solvent gave a residue, which was crystallized from diisopropyl ether to afford Boc-D-Trp(CH3)-OH (9.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
3,4-dichloroaniline (150 g) was dissolved in 1.0 L TBME and the solution was cooled to 10° C. Sodium hydroxide (140.7 g of a 30% aqueous solution) was added under mechanical stirring. Pivaloyl chloride (125.9 mL) was added dropwise while keeping the internal temperature under 35° C. After the addition, the temperature of the reaction was maintained at 30-35° C. for a further 30 min. The reaction mixture was then allowed to cool to room temperature and subsequently kept at 0-5° C. for 1 h. The resulting precipitate was filtered of and washed with 600 mL water/MeOH (90/10) and then with 900 mL water. The resulting solid was the dried in a vacuum oven at 55° C. for 4 days. Yield: 162 g. 1H-NMR (DMSO-d6) δ 9.46 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.65 (dd, J=9.0. 2.4 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 1.22 (9H, s).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:14])[NH:12][CH2:11][CH:10]([CH3:13])[O:9]1.C(N(CC)CC)C.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>O>[CH3:7][C:8]1([CH3:14])[N:12]([C:24](=[O:25])[CH:23]([Cl:27])[Cl:22])[CH2:11][CH:10]([CH3:13])[O:9]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1CNC(C)(C)O1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
Eighteen (18) milliliters of a benzene solution containing 4.6 g. of 2,2,5-trimethyl oxazolidine was added to 25 ml. of benzene and 4.5 g. of triethylamine. Five and nine-tenths (5.9 g.) grams of dichloroacetyl chloride was added dropwise with stirring and cooling in an ice bath. When reaction was complete the mixture was poured into water and the benzene layer separated, dried over anhydrous magnesium sulfate and the benzene removed under vacuum. Yield was 7.7 g. of an oil, nD30 =1.4950.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])=[CH:9][C:8]=2[C:33]([F:36])([F:35])[F:34])=[CH:4][CH:3]=1.[CH:39]([CH:41]=[O:42])=[O:40].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:39]([OH:40])[CH:41]([OH:42])[N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]6[NH:30][N:31]=[CH:32][C:25]=56)=[CH:21][CH:22]=4)[C:14]3=[O:15])=[CH:9][C:8]=2[C:33]([F:35])([F:36])[F:34])=[CH:37][CH:38]=1
Reactant: O=CC=O
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1N(c2ccc(Oc3ccnc4[nH]ncc34)cc2)C(O)C(O)N1c1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
1-[4-(4-Fluorophenoxy)-3-trifluoromethyl-phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (50 mg, 0.15 mmol) was dissolved in ethanol (5 mL), and 40% glyoxal (35 μL) and a 1 N sodium hydroxide aqueous solution (30 μL) were added thereto. The resulting mixture was stirred at 70° C. for 4 hours. The reaction solution was concentrated and then purified by reverse-phase HPLC (ODS column, 0.05% TFA-containing water/acetonitrile system, 5% to 95% linear gradient) to give the target product (9 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]1[NH:16]C(=O)OC(C)(C)C.Cl>O1CCOCC1>[NH2:16][CH:3]1[C:2]([CH3:24])([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CCCC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCCN(c2ccccc2)C(=O)C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a round bottom flask was added tert-butyl 4,4-dimethyl-2-oxo-1-phenylazepan-3-ylcarbamate (6.5 mg, 0.020 mmol) and 4 N HCl in dioxane (1 mL). The reaction was stirred at rt for 1 hr. The solvent was removed to give 3-amino-4,4-dimethyl-1-phenylazepan-2-one (3.8 mg, 0.016 mmol, 84% yield) as the mono hydrochloride salt. Anal. Calcd. for C14H20N2O m/z 232.2. found: 233.2 (M+H)+.
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]2[CH2:71][CH2:70][CH:69]([N:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][C:66]=2[C:78]=1[NH2:79]>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:79][C:78]2[C:66]3[CH2:67][CH2:68][CH:69]([N:72]4[CH2:73][CH2:74][O:75][CH2:76][CH2:77]4)[CH2:70][CH2:71][C:65]=3[CH:64]=[CH:63][C:62]=2[O:61][CH3:60])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCC(N1CCOCC1)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford 5-Chloro-N*2*-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine. LC/MS (ESI): 546.26. 1H NMR (400 MHz, DMSO, d6) δ 8.18 (m, 1H), 8.31 (m, 1H), 7.93 (s, 2H), 7.57 (m, 2H), 7.16 (m, 2H), 6.89 (m, 2H), 6.61 (s, 1H), 3.70 (s, 3H), 3.40 (m, 2H), 3.09 (m, 5H), 2.89 (m, 2H), 2.67 (m, 2H), 2.32 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2)[CH:2]=[CH2:3].[Br:21][C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=1)[C:14]([CH3:19])=[CH:13]2)[CH3:20])[CH:2]=[CH2:3]
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)cc2c1
Product: C=CCN(C)CCCCOc1ccc2c(c1)cc(C)n2-c1ccc(Br)cc1

Procedure:
In analogy to example 9.1, Allyl-methyl-[4-(2-methyl-1H-indol-5-yloxy)-butyl]-amine and 1-bromo-4-fluorbenzene were converted to yield Allyl-{4-[1-(4-bromo-phenyl)-2-methyl-1H-indol-5-yloxy]-butyl}-methyl-amine as orange viscous oil, MS: 426 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([OH:23])=[C:6]([C:8](=[N:16][CH:17]=[CH:18][CH2:19][C:20](O)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([OH:23])=[C:6]([C:8](=[N:16][CH:17]=[CH:18][CH2:19][C:20]([NH2:27])=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cl)cc(C(=NC=CCC(=O)O)c2ccc(Cl)cc2)c1O
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=NC=CCC(N)=O)c2ccc(Cl)cc2)c1O
Reaction time: 2 h

Procedure:
To 3.3 g of the acid obtained in Example 1, dissolved in 100 ml of tetrahydrofuran (THF), 1.6 g of carbonyldiimidazole is added and the mixture is stirred for 2 hrs. A solution is prepared of ammonia gas in 250 ml of anhydrous THF, into which the first solution obtained is introduced slowly. The mixture is stirred for 3 h and left to stand overnight. It is evaporated to dryness under reduced pressure and the residue is distributed between 150 ml of CH2Cl2 and 100 ml of water. The organic phase is decanted, dried over MgSO4, filtered and evaporated to dryness. An oil is obtained which is purified by chromatography on silica (eluent: ethyl acetate). The 3 final fractions containing the products are dried over MgSO4. The fractions are filtered and the filtrates evaporated to dryness. One of the 3 residues obtained, a mixture of both cis (32%) and trans (68%) isomers, is recrystallised in a mixture of ether and petroleum ether.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:3][C@H:2]([C@@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCCCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: CCCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
This compound was prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with pentanal.
Reaction SMILES: C([N:8]([CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17])[CH2:9][CH2:10][O:11][CH3:12])C1C=CC=CC=1.[ClH:18]>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:18].[CH3:12][O:11][CH2:10][CH2:9][NH:8][CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17]
Reactant: COCCN(Cc1ccccc1)CC1CC1C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: COCCNCC1CC1C
Reaction time: 16 h

Procedure:
Coupling In a 500 mL flask methoxyacetic acid (2.24 g, 24.8 mmol), N-benzyl-1-(2-trans-methylcyclopropyl)methanamine hydrochloride (5.0 g, 23.6 mmol) and DIPEA (13.4 g, 104 mmol) were dissolved in 300 mL of dichloromethane. To this solution at rt BOP (11.0 g, 24.8 mmol) was added as a solid portionwise and stirred 15 minutes. The reaction mixture was evaporated ini vacuo. Purification by flash chromatography (25-35% ethyl acetate:hexanes) provided a mixture of cis and trans amides as a clear oil: ES MS (M+H)=248.1. Step B: Reduction A 500 mL flask charged with N-benzyl-2-methoxy-N-(2-methoxycyclopropyl)methyl acetamide (from step A, 7.75 g, 31.3 mmol) in THF (100 mL) was added BH3-THF (1.0 M, 94 mL, 94 mmol) dropwise via an addition funnel. Upon complete addition (10 min.) the mixture was refluxed for 14 h. The mixture was allowed to cool to rt and quenched carefully with MeOH (15 mL). The mixture was then treated with 15 mL concentrated HCl and heated to reflux for 5 h. The reaction was evaporated in vacuo and partitioned between ethyl acetate and 20% NaOH solution. The aqueous layer was washed with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase LC gave N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 3.70 (bq, J=13.5 Hz, 2H), 3.49 (bs, 2H), 3.31 (s, 3H), 2.75 (bm, 2H), 2.51 (m, 1H), 2.31 (m, 1H), 1.03 (d, J=5.86, 3H), 0.59 (m, 1H), 0.48 (m, 1H), 0.22 (m, 2H). ES MS (M+H)=234.2. Step C: Hydrogenation A degassed solution of N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine (4.89 g, 20.9 mmol) in 150 mL ethyl alcohol was treated with palladium hydroxide (20% on carbon, 0.29 g) and hydrogen chloride (5.24 mL of a 4M solution in dioxane, 21 mmol) then placed under a hydrogen atmosphere for 16 hours. The reaction mixture was degassed with nitrogen, filtered through celite, washed with methanol and evaporated in vacuo to give (2-methoxyethyl)[(2-methylcyclopropyl)methyl]amine hydrochloride as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 3.65 (m, 2H), 3.41 (s, 3H), 3.21 (m, 2H), 2.92 (m, 2H), 1.09 (d, J=5.68 Hz, 3H), 0.80 (m, 2H), 0.57 (m, 1H), 0.46 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[C:10]([F:29])=[CH:11][C:12]([F:28])=[C:13]([C@:15]4([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=O)[NH:16]4)[CH:14]=3)[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[C:10]([F:29])=[CH:11][C:12]([F:28])=[C:13]([C@:15]4([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=[S:41])[NH:16]4)[CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)c(F)cc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)c(F)cc2F)C1(F)F
Yield: 87.2 %

Procedure:
The reaction of (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (164 mg, 359 μmol) with Lawesson's reagent (145 mg, 359 μmol) in 1,4-dioxane (3.5 ml) yielded the (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (148 mg, 87% yield) as a white solid. MS (ISP): m/z=473.0 [M+H]+ and 475.1 [M+2+H]+.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[OH:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][N:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccc(N2CCC(O)(c3ccccc3)CC2)c2ccccc12
Temperature: 110 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
1-Cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) was dissolved in pyridine (1 mL). 4-Hydroxy-4-phenylpiperidine (83 mg, 0.467 mmol) was added and the reaction mixture was shaken at 110° C. for 3 days in a sealed vial. The reaction mixture was concentrated and re-suspended in 2 M HCl (1 mL). The product mixture was extracted with ethyl acetate (2×1 mL), and the combined organic phases were concentrated. The residue was purified by preparative reversed phase HPLC to give the title compound (14 mg, 36% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[CH2:16][CH3:17].O>ClCCCl.C(Cl)Cl>[OH:24][C:19]1[C:18]([CH2:15][CH2:16][CH3:17])=[CH:23][C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:5])=[CH:21][CH:20]=1
Reactant: CCCc1ccccc1O
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(C(=O)c2ccccc2F)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0° C. suspension of 2-fluorobenzoyl chloride (1.3 mL, 11.03 mmol) in 15 mL of 1,2-dichloroethane was treated with aluminum chloride (1.0 g, 7.35 mmol). The suspension was vigorously stirred for 15 minutes. A solution of 2-propylphenol (1.0 g, 7.35 mmol) in 5 mL of 1,2-dichloro-ethane was added dropwise. The mixture was allowed to stir and gradually warm to 25° C. over 6 hours. The mixture was slowly added to a stirred mixture of water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated to a solid. The crude residue was purified via flash chromatography on silica gel (15% ethyl acetate/hexane eluent) to afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:21])(=O)=O)=CC=1.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([F:21])[S:7][C:6]=2[CH:10]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cc2ccc(Br)cc2s1
Yield: 32.5 %

Procedure:
Using analogous reaction condition and reagents as described Example 20 for the preparation of I-20a, 6-bromo-benzo[b]thiophene (I-25c: 0.5 g, 2.347 mmol) in dry THF was reacted with N-fluorobenzenesulfonimide (1.33 g, 4.22 mmol), n-butyl lithium (1.76 ml, 3.52 mmol), diisopropyl amine (0.57 ml, 3.99 mmol) to afford crude product. Purification by column chromatography on silica gel (100% hexane) afforded 176 mg of the product (33% yield).