Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.CN(C)[CH:31]=[O:32]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:31]=[O:32])=[CH:17][CH:16]=2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N(c2ccc(C=O)cc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1.76 g (11.5 mmols) of phosphorus oxychloride was dropped in anhydrous dimethylformamide under agitation at room temperature, into which 25 ml of anhydrous dimethylformamide solution of 1.75 g of N,N-di(4-methoxyphenyl)aniline ((36)-2) was further dropped, following by raising the reaction temperature and agitating at 70° C. for 90 minutes.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11](Cl)[C:12]3[S:17][C:16]([NH2:18])=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23]>>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23])=[N:10][C:9]([S:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CC(C)C(N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Product: CC(C)C(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 100 °C
Yield: 24.1 %

Procedure:
5-Phenylmethylthio-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamine (WO 00/09511) (100 mg, 0.32 mmol) and DL-2-amino-3-methyl-1-butanol (253 μL, 2.3 mmol) were suspended in anhydrous tetrahydrofaran (4 mL) and the reaction tube was capped. The solution was heated at 100° C. for 24 hours and was then allowed to cool down to room temperature. The solvent was evaporated in vacuo and the crude product was flash chromatographed on silica (eluent—ammonia:ethanol:dichloromethane, 1:8:91) followed by a second chromatography (gradient eluent—ammonia ethyl acetate: dichloromethane, 1:59:40 to 1:99:0) resulting in 29 mg (24% yield) of the title compound as a white solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[SH:10].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>C(O)C.O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10][C:12]1[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
Sodium metal (0.126 g, 5.5 mmol) was dissolved in absolute ethanol (10 mL) and to the resulting solution was added 2,3-dichlorobenzenethiol (0.895 g, 5 mmol). Ethyl 5-chloro-4-nitrothiophene-2-carboxylate (1.18 g, 5 mmol) was added and the reaction mixture was stirred for 1 hour at ambient temperature and was allowed to stand overnight. After this time, the mixture was diluted with water (30 mL) and the resulting precipitate was collected by filtration and dried in vacuo at 40° C. for 1 hour. Initial analysis showed some minor impurities so the crude material was stirred in absolute ethanol (10 mL) for 30 min, collected by filtration and dried in vacuo at 40° C. for 1 hour to afford the title product as a white solid (0.67 g, 35% yield). 1H NMR (CDCl3) δ: 8.18 (1H, s), 7.71 (2H, m), 7.31 (1H, m), 4.31 (2H, q, J=7.11 Hz), 1.33 (3H, t, J=7.11 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C:8](=[O:24])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[K+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6](=[O:25])[CH2:7][C@@H:8]([OH:24])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)CC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)[C@H](O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution of t-butyl-(4S)-4-(N-benzyloxycarbonylamino)-5-methyl-3-oxohexanoate (6.0 g, 17.1 mmol) in 70 ml ethanol at 0° C. was added potassium borohydride (3.23 g, 58.8 mmol). After stirring for 4 h at 0° C. and 12 h at room temperature, the reaction mixture was acidified with glacial acetic acid to pH 4 and concentrated in vacuo. The residue was dissolved in a mixture of 200 ml ethyl acetate and 200 ml water. After additional washings of the aqueous phase with ethyl acetate (3×50 ml), the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate-hexane (1:4) as eluent to give the alcohol as a white solid (5.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:34]([NH:38]O)([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CC(C)(C)NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-cl[1]-benzazepine-4,10(1H,9H)-dione (400 mg, 1.37 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (334 mg, 2.06 mmol) in N,N-dimethylformamide (16 mL) was stirred for 1 hour. In one portion, N-tert-butylhydroxylamine hydrochloride (516 mg, 4.11 mmol) was added and the solution was stirred for 17 hours at room temperature. To the resulting solution was added water (20 mL). The insoluble material was filtered and washed with hot methanol (3×20 mL) to give the title compound (300 mg, 61% yield, m.p. 258° C.).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([OH:24])[C:21]#[C:22][CH3:23].[OH-].[Na+].Cl>O>[CH2:20]([O:24][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:21]#[C:22][CH3:23]
Reactant: CC#CCO
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC#CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 80 °C
Yield: 300.6 %

Procedure:
To a solution of [4-(4-fluoro-benzoyl)-piperidin-1-yl]-acetic acid (561 mg, 2.11 mmol) in water (10 mL) and was added 2-butyn-1-ol (3.71 g, 52.9 mmol) followed by a solution of 4N NaOH (3.44 mL, 13.8 mmol). The reaction was heated up to 80° C. for 72 hours. The reaction was acidified using 2N HCl to pH 5, then the solvent was then removed under vacuum to afford the crude title compound (2.0 g). LRMS m/z: ES+=315.9 (M+H), retention time 1.52.
Reaction SMILES: [NH2:1][C:2]1[NH:3][N:4]=[C:5]([CH3:7])[CH:6]=1.C(O[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)C1C=CC=CC=1>>[C:25]1([C:17]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]3[NH:3][N:4]=[C:5]([CH3:7])[C:6]=23)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OC(=Cc1ccncc1)c1ccccc1)c1ccccc1
Reactant: Cc1cc(N)[nH]n1
Product: Cc1n[nH]c2nc(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)c12
Yield: 16 %

Procedure:
Following a similar procedure to that described in example 1 method B, but using 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole and 1-phenyl-2-(4-pyridyl)vinyl benzoate (obtained in reference example 5) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl 4-fluorobenzoate, the title compound was obtained in solid white form (yield: 16%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:16]=1)=[C:6]1[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@H:8]([CH2:14]Cl)[O:7]1.[NH:17]1[CH2:22][CH:21]=[C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1>CS(C)=O.C(OCC)(=O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:14][CH:8]3[O:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]5[NH:3][C:2]([CH3:1])=[N:16][C:5]5=4)[O:10][CH2:9]3)[CH2:18][CH:19]=2)=[CH:24]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1nc2c3c(ccc2[nH]1)OC[C@H](CCl)O3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 105 °C

Procedure:
A mixture of 0.50 g (2.1 mmole) of [(8R)-2-methyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl chloride and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 100-110° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give the desired compound as the free base. Recrystallization from ethanol with the addition of 0.12 g of fumaric acid gave 0.11 g of the (S)-enantiomer of the title compound as a yellow solid fumarate, one-quarter hydrate, m.p. 219-222° C.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:18])[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].[Cl-].[NH4+]>O1CCCC1>[CH3:9][C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:7](=[O:18])[CH3:1]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Methyl magnesium bromide (3.0M solution in diethyl ether, 4.3 ml, 12.9 mmol) was added to a stirred solution of tert-butyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate (Tetrahedron: Asymmetry 1996, 7, 985) (1 g, 4.3 mmol) in anhydrous tetrahydrofuran (20 ml) at −60° C. under a nitrogen atmosphere. The mixture was allowed to warm to 0° C. and to then room temperature and was stirred at room temperature for 1 hour. Aqueous saturated ammonium chloride was added and aqueous phase was extracted with diethyl ether (2×76 ml). The combined organic extracts were then washed with saturated aqueous ammonium chloride solution and brine. The organic phase was then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol (99:1 to 98:2), to afford the title compound as a colorless solid, 412 mg, 51% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:11])=[O:10].[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl.ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10]
Reactant: O=S(=O)=O
Reactant: O=C(Cl)Cc1ccccc1F
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1F)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-(2-fluorophenyl)acetyl chloride (1.73 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. This mixture was stirred at room temperature for eighteen hours and evaporated to a yellow gum. νmax. (CHCl3) 1805 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:6]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C:5]([OH:17])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH:10]([C:11]([Cl:12])([Cl:13])[Cl:14])[NH:9][C:7](=[O:8])[C:6]=2[CH:16]=1
Reactant: Nc1ccc(O)c(C(=O)NC(O)C(Cl)(Cl)Cl)c1
Agent: O=S(=O)(O)O
Product: Nc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Reaction time: 0.5 h

Procedure:
5-Amino-N-(1-hydroxy-2,2,2-trichloroethyl)salicylamide (23.0 g.) and concentrated sulphuric acid (115 ml.) were heated on a steam bath for 1 hour, then poured onto ice (1 l.). The resulting mixture was stirred for 30 minutes and filtered. The filtrate was adjusted to pH 5 with 5 N sodium hydroxide solution and stirred for 30 minutes, and the precipitated product was filtered off, washed with water, and dried at 60° C. to give 6-amino-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 172°-174° C.
Reaction SMILES: C(OC(OCC)C[N:6]([C:16](=O)[CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>O>[ClH:22].[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:16][CH:17]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CCOC(CN(C(C)=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 84.2 %

Procedure:
A mixture of N-acetyl-p-nitroanilinoacetaldehyde diethyl acetal (1 g), 3,4-dihydroxyphenethylamine hydrochloride (1 g), n-butyl alcohol (10 ml) and water (1.5 ml) was refluxed for 7 hours. In the course of the reaction, the above-mentioned acetal (2.5 g) was added to the mixture, twice in 0.5 g portions and five times in 0.3 g portions, one every hour. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was pulverized by adding ether and the powder was collected by filtration, washed with ethyl acetate and water and dried to give 1-(p-nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g), mp 238° to 239° C. (dec).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([P:22](Cl)(Cl)=[O:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: O=P(Cl)(Cl)c1ccc(F)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccccc1
Yield: 30 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-fluorophenyl phosphonic dichloride to yield a pale yellow solid. The yellow solid was recrystallized from ethyl acetate to yield 1-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.9 g, 30% yield) as white needles having a melting point of 119°-120° C. and the following analysis:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[NH:23][C:24](=[O:26])[CH3:25])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[C:24]([NH:23][CH:17]1[CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21][CH:16]1[C:14]([N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:15])(=[O:26])[CH3:25]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1NC(C)=O)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC1CC(C)CCC1C(=O)N(c1cc(-c2ccccc2)sc1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.2 %

Procedure:
3-[(2-Acetylamino-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (8.5 mg, 0.019 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (250 ul) and then LiOH 1N (22 ul, 0.023 mmol) was added. After 22 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated to give 7.5 mg (91%) of 3-[(2-Acetylamino-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 12).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[C:24](Cl)[N:23]=1>C(O)CC(C)C>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:24]3[N:23]=[C:22]([NH2:21])[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(N)c2cc1OC
Temperature: 120 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
Compound 49 (0.57 g, 2.1 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.45 g, 1.9 mmol) in isoamyl alcohol (3-methyl-1-butanol) (20 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.57 g (59%) of the title compound: TLC (Rf =0.41; 80% EtOAc/hexanes); 1H NMR (DMSO) δ 12.20 (br s, 1H), 8.66 (br, 2H), 7.76 (s, 1H), 7.66 (d, 2H, J=8.7), 7.53 (s, 1H), 6.67 (d, 2H, J=8.7), 6.51 (d, 1H, J=7.4), 4.56 (d, 2H, J=13.6), 3.90 (s, 3H), 3.86 (s, 3H), 3.76 (m, 1H), 3.46 (m, 2H), 2.07 (d, 2H, J=11.1), 1.52 (s, 9H), 1.44 (m, 2H); 13C NMR (DMSO) δ 165.3, 161.4, 155.3, 151.4, 151.1, 146.8, 136.4, 131.0, 117.8, 111.3, 105.0, 101.6, 99.2, 79.1, 56.3, 56.1, 48.0, 43.4, 31.0, 28.1; HRMS (FAB) m/z 480.2616 (M+H)+ (C26H33N5O4 requires 480.2611); Anal. (C26H33N5O4 ·1HCl) C, H, N.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C@H:20]([C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)[CH3:21])=[N:24][CH:25]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 220 mg (0.51 mmol) dissolved in toluene (5 mL) were added 0.17 mL (1.53 mmol) of 1-chloroethyl chloroformate and 0.27 mL (1.53 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 110 mg (62%) of the title compound as a light yellow oil. ES-MS m/e: 337.1 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.B1(C=C)OB([CH:26]=[CH2:27])OB(C=C)O1.C1C=CN=CC=1>COCCOC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([CH:26]=[CH2:27])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(=O)OCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(COC(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Tetrakis-(triphenylphosphine)palladium(0) (5 mol %, 62.3 mg) was added to a solution of (6-chloropyridin-3-yl)methyl acetate (200 mg) in DME (10 mL) and the solution left to stir at room temperature (20 min.). K2CO3 (0.16 g, 1.1 eq.), water (3 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (0.29 g, 1.1 eq.) were then added to the solution and the resultant mixture heated at reflux (24 hrs). The mixture was then cooled to room temperature and extracted with diethyl ether (100 mL) and the extract washed with water (30 mL). The diethyl ether extract was dried over MgSO4 and then diluted with hexane (100 mL). The solution was filtered through aluminium oxide (2 g) and the eluent concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (10.80% EtOAc/Pet ether) to yield (6-vinylpyridin-3-yl)methyl acetate as a colourless oil (172 mg, 90%). 1H NMR, 400 MHz (CDCl2): 9.16 (d, 1H, H-6, J=2.3 Hz), 8.24 (dd, 1H, H-4, J=2.3 and 8 Hz), 7.39 (d, 1H, H-3, J=8 Hz), 6.85 (dd, 1H, H-A, J=11 and 17.6 Hz), 6.33 (dd, 1H, H—C, J=1.2 and 17.6 Hz), 5.61 (1H, H—B, J=1.2 and 11 Hz), 4.40 (m, 2H, —CH2), 1.40 (m, 3H, —OCH3). 13C NMR, 100 MHz (CDCl3): 165.23, 159.07, 150.79, 137.56, 136.18, 124.72, 120.91, 120.62, 61.28, 14.25. ESI-HRMS Expected for C10H11NO2=177.0790. Found M+H=178.0868.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2].B.C1C[O:38]CC1.C[N+]([O-])(C)C.O>COCCOCCOC.C1COCC1>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH2:12][CH2:13][OH:38])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: C=CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Reactant: C1CCOC1
Agent: B
Agent: C[N+](C)(C)[O-]
Solvent: O
Solvent: COCCOCCOC
Product: CC(=O)O[C@H]1[C@H](CCCO)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A solution of 629 mg (1.41 mmol) of 29 in anhydrous diglyme (21 mL) was stirred at 0° C. as 1.49 mmol of borane-THF (1.49 mL of a 1 M solution in THF) was added. Reaction was stirred at 0° C. for ½ h the allowed to warm to rt and stir for 2 h. To this was added 660 mg (5.96 mmol) of trimethylamine oxide and reaction was stirred and heated at 150° C. for 2 h, cooled to rt, poured into H2O (150 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with 10% sodium metabisulfite (70 mL), H2O (70 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 3×22 cm column of silica gel using hexanes/EtOAc (1.5:1) as eluent gave 530 mg (81%) of 30 as a white solid. Data for 30: TLC, T-6, Rf0.34. 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H, H-18), 2.09 (s, 3H, Oac), 2.85 (m, 2H, H-6), 3.85 (t, 2H, J=5.7 Hz, —CH2O—), 4.63 (d, 1H, J=7.8 Hz, H-17α), 5.04 (s, 2H, benzylic), 6.72 (d, 1H, J=2.6 Hz, H-4), 6.78 (dd, 1H, J=8.2, 2.6 Hz, H-2), 7.19 (d, 1H, J=2.6 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C30H38O4Na (M+Na+) m/e 485.2668, found m/e 485.2679.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][C@H:11]1[C@@H:16]([O:17][CH3:18])[CH2:15][CH2:14][CH2:13][N:12]1[C:19]([C:21]1[N:22]=[C:23]([CH3:33])[S:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:20]>>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][C@H:11]2[C@@H:16]([O:17][CH3:18])[CH2:15][CH2:14][CH2:13][N:12]2[C:19]([C:21]2[N:22]=[C:23]([CH3:33])[S:24][C:25]=2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:20])=[N:7][CH:6]=1
Reactant: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-cis-(2-(aminomethyl)-3-methoxypiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 476.0 (M+H).