Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1[C:10]2(CCC(=O)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To solution of methyltriphenylphosphonium bromide (17 g, 1.5 eq.) in THF (100 mL) at 0° C. was added dropwise n-butyllithium (2.5 M in hexanes, 18 mL, 1.4 eq.) and the resulting mixture was stirred for 1 h. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.0 g, 32 mmol, 1.0 eq.) in THF (10 mL) was then introduced dropwise and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of sat. NaHCO3 and the separated aqueous layer was extracted with 4×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 10% EtOAc/hexanes) to give 8-methyene-1,4-dioxa-spiro[4.5]decane (3.92 g, 79%).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (76 mg, 0.264 mmol), 3-(pyrimidin-2-yl)aniline (64 mg, 0.375 mmol), K2CO3 (90 mg, 0.652 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg, 0.131 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 441.2 (M+H); UV 201.1, 249.3, 301.5 nm; t 0.462 min.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1.[OH-].[Na+]>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
In 300 ml of ethanol is dissolved 5.8 g of sodium, and 40 g of diethyl malonate is added to the solution, followed by stirring. 3-(1-Benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g) is added to this mixture followed by refluxing with stirring for 2 hours. After cooling, 1 l of water is added to the reaction solution, which is then extracted with 500 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylvalearate as an oily material. This product is dissolved in 200 ml of ethanol, and a solution of 34 g of sodium hydroxide in 200 ml of water is added dropwise to the solution with stirring. After the addition is completed, 300 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqueous layer is made acidic with conc. hydrochloric acid, followed by extraction with 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oily material. This product is heated at 160° to 170° C. with stirring for 45 minutes to give 50 g of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid as an oily material.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[S:13](=O)(=[O:16])([OH:15])[OH:14].ClS(O)(=O)=O.Cl>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:5]=1[NH2:4]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)Cl
Product: Nc1c(Cl)cc(Cl)cc1S(=O)(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
204 parts of the crude 2,4-dichloroacetanilide are added to 300 parts of 100% strength sulfuric acid, while stirring. Thereafter, the mixture is heated further to 130° C., and 235 parts of chlorosulfonic acid are added dropwise at this temperature in such a manner that the hydrogen chloride gas liberated can readily be removed. Stirring is then continued at from 135° to 140° C. until the sulfonation is complete, this taking about 1 hour. The mixture is then left to cool to 50°-80° C., and is poured into 1300 parts by volume of water. After steam distillation for a short time, 10 parts of pure 2,4,6-trichloroaniline are obtained, as a by-product, in the distillate. The reaction mixture is then cooled to room temperature, and precipitated 2,4-dichloroaniline-6-sulfonic acid is filtered off and washed with dilute hydrochloric acid. 204 parts of 2,4-dichloroaniline-6-sulfonic acid (calculated as 100% pure) are obtained as a colorless aqueous paste, which can be used in moist form for diazotizations. H-NMR in D2O: 7.3 ppm, 7.6 ppm, J: 3 Hz (as the ammonium salt).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[N:15]([CH:17]([CH3:18])[CH3:19])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(Cc1ccccc1)C2
Yield: 27.7 %

Procedure:
The title compound (72 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 146 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C22H24FN3, 349.20; found, m/z 350.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.57 (m, 2H), 7.55-7.53 (m, 3H), 7.43-7.40 (m, 2H), 7.32-7.27 (m, 2H), 4.59-4.34 (m, 5H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.90-2.85 (m, 2H), 1.43-1.36 (m, 6H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:9][OH:10])(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH2:7][C@H:8]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CO)c1ccc2ccccc2c1

Procedure:
(R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butyl ester (2.5 g) and 9 mL of 4 N HCl in ethyl acetate at 50° C. was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the title compound (1.2 g) as a solid which was used in the next step without further purification.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42]N(C)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]
Reactant: NCCCCCCC(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCCCCC(=O)O)C1
Yield: 5 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 7-amino-heptanoic acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (11.2 mg, 5% yield). 1H NMR (500 MHz, CDCl3) δ: 11.95 (bs, 1H), 11.00 (s, 1H), 7.61 d, 1H, J=8.24), 7.52 (s, 1H), 7.25 (s, 1H), 4.58 (s, 2H), 4.04 (s, 2H), 3.36 (m, 2H), 2.98 (s, 3H), 2.18 (t, 2H, J=7.33), 1.48 (m, 4H), 1.26 (m, 4H). HRMS (M+H) calcd for C20H25N2Cl2O5: 443.1140. found: 443.1153.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH:6]([CH3:23])[CH2:7][C@H:8]3[C@H:16]4[C@@:12]([CH2:18][CH3:19])([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:20]=2[CH2:21][CH:22]=1.Cl.O>CO.[Cl-].[Na+].O>[CH2:18]([C@:12]12[CH2:11][CH2:10][C@@H:9]3[C@@H:20]4[C:5]([C@@H:6]([CH3:23])[CH2:7][C@H:8]3[C@@H:16]1[CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:4][C:3](=[O:2])[CH2:22][CH2:21]4)[CH3:19]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](C[C@H](C)C4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 31.4 %

Procedure:
Stir dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (1.0 g) in methanol (54 cc) containing concentrated hydrochloric acid (3.6 cc) and water (2.4 cc) under nitrogen for 1.5 hours. Pour into brine, extract with ether and isolate the crude product. Chromatograph on Grade I neutral alumina (50 g) and recrystallize from ether-hexane to obtain the title compound (0.30 g), m.p. 127°-130°, λ max. KBr 2.98 μ, 6.03 μ; λ max. EtOH 240 mμ (ε16,500).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+]>CN(C)C=O.O>[F:16][C:13]1[CH:14]=[CH:15][C:7]2[NH:6][C:3](=[O:4])[CH2:2][O:10][C:9](=[O:11])[C:8]=2[CH:12]=1
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)c2cc(F)ccc2N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2.52 g(13.75 mmol) of bromoacetyl bromide was added for 10 min below 40° C. to the solution having 1.94 g(12.5 mmol) of 2-amino-5-fluorobenzoic acid dissolved in 4 ml of dimethyl formamide. The mixed solution was stirred for 30 min, and the solution having 1.12 g of sodium hydroxide dissolved in 28 ml of water was added. The mixture was slowly heated to 60° C. for 1 hr, then maintained at about 60° C. for 1 hr, and cooled to 5° C. Finally, a crystalline solid of 7-fluoro-4,1-benzooxazepine-2,5-(1H, 3H)-dione of melting point 186° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1ccc2ncnc(Cl)c2c1
Product: COc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Yield: 77 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 77% yield from 6-chloro-indoline and 4-chloro-6-methoxy-quinazoline. (M.P. 243° C.; LC-MS: 312 (MH+)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
4-bromo-4′-fluorobenzophenone was synthesized by the Friedel-Crafts acylation of fluorobenzene with 4-bromobenzoyl chloride. More specifically, fluorobenzene (117 grams, 1.2 mol) and 4-bromobenzoyl chloride (39.8 grams, 0.18 mol) was charged to a 250 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was then cooled to 0° C. and anhydrous AlCl3 (27 grams, 0.20 mol) was added. The mixture was stirred for 15 minutes at 23° C. for 16 hours. The resulting slurry was poured into 2 liters of water acidified with HCl. The organics were extracted with methylene chloride and subsequently dried over MgSO4. The slurry was filtered and the methylene chloride was removed under reduced pressure. Recrystallization from ethanol gave 43.4 grams (86 percent yield) of the desired crystalline product.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:43][CH2:44][F:45]>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:43][CH2:44][F:45])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: FCCBr
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(CCF)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (85 mg, 0.18 mmol) was dissolved in 3 mL NMP with DIEA (95 μL, 0.54 mmol). To it was added 1-bromo-2-fluoroethane (230 mg, 1.8 mmol). The mixture was stirred at RT for overnight. The reaction was about 70% completion. It was quenched with TFA and concentrated in vacuo. The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (53 mg). MS found for C26H28F3N5O as (M+H)+ 484.4. UV: λ=256 nm. 1H NMR: (CD3OD) δ 8.19 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.19-7.14 (3H, m), 7.10 (1H, m), 5.82 (1H, s), 4.97 (1H, m), 4.85 (1H, m), 4.55 (2H, s), 3.77 (2H, d, J=12.0 Hz), 3.62 (1H, m), 3.55 (1H, m), 3.28 (2H, m), 3.00 (1H, m), 2.15 (4H, m) ppm.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[N:1]1([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]([NH:20][NH2:21])=[O:17])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Temperature: 25 °C
Yield: 68 %

Procedure:
Methyl 5-(morpholin-4-ylcarbamoyl)thiophene-2-carboxylate (237 mg, 0.87 mmol) in ethanol (6.0 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature and the solvent was evaporated at 40° C. 5 mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 160 mg of the desired product (yield 68%).
Reaction SMILES: C(O[C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:28][CH2:27][NH:26][C:4]([C:6]2[C:22]3[C:10](=[C:11]([CH3:25])[C:12]4[N:13]([CH3:24])[C:14]5[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=5[C:20]=4[CH:21]=3)[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Reactant: NCCN1CCCC1
Product: Cc1c2ccnc(C(=O)NCCN3CCCC3)c2cc2c3cc(O)ccc3n(C)c12
Temperature: 120 °C

Procedure:
0.4 g (1.198 mmol) of the ester obtained in Step A of Example 11 are dissolved in 7.5 ml of 1-(2-aminoethyl)pyrrolidine under an argon atmosphere. The mixture is heated at 120° C. for 16 hours.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:26])[CH3:27])[CH:31]([CH3:32])[CH3:33])=[N:10][CH:11]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
Trimethylaluminium (2M solution in toluene) (2.99 mL, 5.98 mmol) was added to a solution of 5-chloropyridin-2-amine (0.769 g, 5.98 mmol) in toluene (20 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (1 g, 2.99 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (0.935 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 1.05-1.13 (24H, m), 3.62-3.67 (3H, m), 3.81-3.84 (1H, m), 4.02-4.06 (1H, m), 4.20 (1H, d), 4.31 (1H, q), 7.65-7.67 (1H, m), 8.22-8.25 (2H, m), 9.23 (1H, s); m/z (ES−) (M−H)−=429; HPLC tR=3.81 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1)[CH3:28]>CN(C=O)C>[CH2:27]([C:29]1([NH:33][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]4)[CH:6]=[N:7][CH:8]=2)[CH2:32][O:31][CH2:30]1)[CH3:28]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CCl)c3)ccc21
Reactant: CCC1(N)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(NCc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)COC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.1 %

Procedure:
To a stirred solution of 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (190 mg, 0.66 mmol) in DMF (5.0 mL) was added K2CO3 (276 mg, 2.0 mmol) and 3-ethyl-oxetan-3-ylamine (415 mg, 3.0 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for additional 12 hours. After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (35 mg, 17.2%) as a light yellow solid. MS: 352.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:22])[CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C1CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)cc23)CC1
Yield: 76.7 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.0 μL (0.10 mMol) cyclopropanecarboxylic acid, 11.4 mg (77%) of the title compound were recovered.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl>C1COCC1.CCOC(C)=O>[CH3:17][O:16][C:12]1[C:11]([CH3:18])=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COc1cccc(C(O)C2CCCCC2=O)c1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCCCC2=O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a solution of 2-[hydroxy-(3-methoxy-2-methylphenyl)-methyl]cyclohexanone (1.85 g) in THF (20 ml) was added conc. HCl (0.5 ml) at 5° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in MeOH (30 ml) and 10% Pd/C (wet) (400 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was pufified by silica gel column chromatography (hexane-EtOAc 12:1 to 8:1) to give 2-(3-methoxy-2-methylbenzyl)cyclohexanone (980.6 mg) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=O.Cl>C1COCC1>[O:18]1[CH2:19][CH2:20][N:15]([CH2:13][CH2:12][C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH2:16][CH2:17]1
Reactant: O=C(Cc1cccs1)N1CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1csc(CCN2CCOCC2)c1
Yield: 60.7 %

Procedure:
Lithium aluminium hydride (1M in diethyl ether, 28.3 ml) was added slowly to a stirred solution of N-[2-(2-thienyl)acetyl]morpholine (3 g) in THF (100 ml). The resultant mixture was heated to 45° C. for 30 minutes. A 2M aqueous hydrochloric acid solution was added dropwise to destroy the excess of reducing agent and the mixture was partitioned between methylene chloride and a 2M aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgSO4) and evaporated to give 2-(2-morpholinoethyl)-thiophene (1.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O.O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 87.1 %

Procedure:
A mixture of 6.0 g of 4-hydroxy-benzaldehyde and 13.58 g of potassium carbonate in 60 ml of N,N-dimethylformamide was treated dropwise at room temperature with a solution of 11.14 g of 3-fluoro-benzylbromide in 30 ml of N,N-dimethylformamide. After 3 h the reaction mixture was diluted with water and extracted with ether. The organic layer was washed with water, dried over magnesium sulphate and evaporated to yield an oil (9.85 g) which crystallised on standing; MS: m/e=230 (M)+. The crude product was used in the next step without further purification.