Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](C(O)([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)C2C=C3C(=CC=2)N(CC2CC2)C(=O)C=C3C2C=CC=C(C#C)C=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C=C3[C:49]([C:50]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([C:65]#[CH:66])[CH:60]=4)=[C:51](C)[C:52](=[O:57])[N:53]3C)=[C:48]([C:67]3N(C)C=NC=3)[C:47]=2O)=CC=1>>[CH3:37][N:33]1[CH:32]=[CH:36][N:35]=[CH:34]1.[CH:48]1([CH2:49][C:50]2([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([C:65]#[CH:66])[CH:60]=3)[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:53][C:52](=[O:57])[CH2:51]2)[CH2:47][CH2:67]1
Reactant: C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Reactant: C#Cc1cccc(-c2c(C)c(=O)n(C)c3cc(-c4ccc(Cl)cc4)c(O)c(-c4cncn4C)c23)c1
Product: C#Cc1cccc(C2(CC3CC3)CC(=O)Nc3ccccc32)c1
Product: Cn1ccnc1
Yield: 62 %

Procedure:
The same procedure that was used in example 3 was followed except 6-[(4-Chloro-phenyl) -hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.80 g, 3.5 mmol) was used in place of 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one to give 6-[Amino(4chloro-phenyl)-(3-methyl-3H-imidazol-4-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.12 g, 62%) as a yellow foam.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.33 min; [M+H]+=492.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@H:36]1[C@H:41]2[CH2:42][C@H:38]([CH2:39][CH2:40]2)[C@H:37]1[CH2:43][OH:44]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][C@@H:36]2[C@H:37]([CH2:43][OH:44])[C@@H:38]3[CH2:42][C@H:41]2[CH2:40][CH2:39]3)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: N[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@H]2[C@@H]3CC[C@@H](C3)[C@H]2CO)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and [(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compound was obtained in 58% purity by HPLC. MS(ESI+): m/z=498.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C(OC(=O)[CH2:8][C:9]1[C:10]([Cl:23])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[CH:14]2)C.C[O-].[Na+]>CN(C)C=O.O>[Cl:23][C:10]1[C:9]([CH2:8][C:1]([NH2:3])=[O:2])=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)nc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 105 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Formamide (118 mg, 2.62 mmol, 3.35 equiv) was added to a solution of (7-chloro-2-dimethylaminomethyl-quinolin-8-yl)-acetic acid ethyl ester (240 mg, 0.78 mmol) in N,N-dimethylformamide (1.0 ml). The solution was heated to 105° C., and then sodium methoxide (5.4 M in MeOH, 0.14 ml, 0.78 mmol, 1.0 equiv) was added dropwise over 20 minutes. After 1 hour, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc and CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of CH2Cl2/MeOH 96:4 to 60:40) afforded the title compound (161 mg, 74%) as a white solid. 1H NMR (400 MHz, d6-DMSO): δ=8.35 (d, J=8.9 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.41 (br s, 1H), 6.88 (br s, 1H), 4.26 (s, 2H), 3.69 (s, 2H), 2.21 (s, 6H). MS (ES+): 278.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=1.[CH3:16][CH:17](O)[CH3:18]>OS(O)(=O)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([O:12][CH:17]([CH3:18])[CH3:16])=[O:11])[CH:8]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1cc(C(F)(F)F)ccc1I
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1cc(C(F)(F)F)ccc1I

Procedure:
5-Trifluoromethyl-2-iodophenylacetic acid (30 g, 91 mmol) is dissolved in 2-propanol (250 mL), a catalytic amount (4 drops) of concentrated H2SO4 added and the solution is stirred and heated to reflux temperature for 12 hours. Solvents are removed by rotary evaporator and the residual oil is purified using flash chromatography (1:4 EtOAc/hexanes) to give isopropyl 5-trifluoromethyl-2-iodophenylacetate as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1>CN(C=O)C>[CH3:49][C:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[C:53]([CH3:62])[O:52][N:51]=1
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (0.012 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 61% yield: LCMS (ESI) m/z 377 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].O=C1C[N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:2]1[CH2:5][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35° C. for 1 h. To this bright yellow reaction mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-1-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35° C. for 12 hours then filtered through a bed of celite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). 1H NMR (400 MHz, CDCl3): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) for C12H13NO2: 203 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:22]([N:10]([CH3:11])[CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])(=[O:24])[CH3:23]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C)C(Cc1ccccc1N)c1sccc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
A stirred, ice water chilled solution of 5.07 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 40 ml of pyridine was treated dropwise with 2.25 g of acetic anhydride. The solution was stirred with cooling for 15 minutes and then at room temperature for 3 hours. After standing overnight, the reaction mixture was decanted into water (200 ml), treated with dichloromethane (100 ml) and basified with 10% sodium hydroxide solution. The aqueous phase was extacted with dichloromethane (150 ml), and the combined organic phase was filtered and concentrated. The resulting solid was stirred with toluene and evaporated to dryness. Recrystallization from propionitrile (14 ml) afforded 3.0 g of N-acetyl-2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 176°-181.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[Cl:11][CH2:12][CH:13]=O>C(O)C>[ClH:11].[CH3:10][C:4]1[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1nc(N)ccc1C#N
Reactant: O=CCCl
Solvent: CCO
Product: Cc1c(C#N)ccc2nccn12
Product: Cl

Procedure:
To a solution of 6-amino-2-methylnicotinonitrile (960 mg) in ethanol (34 ml) was added a 40% aqueous chloroacetaldehyde solution (2.36 ml) at 60° C. The reaction mixture was refluxed for 8 hours. The resulting precipitates were collected by filtration to obtain 5-methylimidazo[1,2-a]pyridine-6-carbonitrile hydrochloride (580 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(C)=C)[C:7]1=[O:18].CO.O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)[nH]c2ccccc21
Temperature: 60 °C
Yield: 93 %

Procedure:
3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (2.2 g, 8.3 mmol) was treated with MeOH (5 mL) followed by water (5 mL) To this heterogeneous reaction mixture was added 37% hydrochloric acid (4 mL). This reaction mixture was heated to 60° C. for 20 min. The reaction remained as a clear homogeneous solution after heating. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.7 g of the desired product as a white solid. This product was used for the next reaction without further purification.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16](Cl)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]1([CH:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN1C(=O)CCC1.C(Cl)Cl>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:45][CH:42]4[CH2:41][CH2:40][CH:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:44][CH2:43]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: NC1CCC(N2CCOCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile (150 mg, 0.38 mmol, 1.00 equiv) in NMP (1 mL) was added triethylamine (310 mg, 3.06 mmol, 8.00 equiv) and 4-(morpholin-4-yl)cyclohexan-1-amine (560 mg, 3.04 mmol, 8.00 equiv) at room temperature. The resulting solution was stirred overnight at 75° C. under nitrogen. After cooling to room temperature, the resulting solution was diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 185 mg (90%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2 (6),8,10-tetraen-3-yl]propanenitrile as a white solid. MS: m/z 542 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:17]1[CH2:16][CH2:15][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[CH2:19][CH2:18]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A flask was charged with 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide (0.035 g, 56 μmol) (as prepared in Example 34, step (b)), NEt3 (31.0 μL, 225 μmol), acetic anhydride (6.5 μL, 62 μmol), and DCM (0.5 mL) and stirred at RT for 1 h. The title compound was eluted from a 10-g SPE cartridge (silica) with 5% MeOH/DCM to give 18 mg (75%) of a white solid. 1H-NMR (400 MHz, CDCl3): δ 9.78 (s, 1H), 8.34 (d, 1H), 7.24 (m, 2H), 7.01 (m, 2H), 4.80 (m, 2H), 3.96. (m, 2H), 3.20 (t, 1H), 2.98 (m, 2H), 2.70 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H), 1.60 (m, 5H), 1.10 (d, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H30N4O3, 435.2 (M+H), found 435.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([OH:10])[CH2:8][OH:9])=[O:4].CC(C)([O-])C.[K+].CO.O>C(O)(CC)(C)C>[OH:9][CH2:8][C@H:7]1[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:10]1
Reactant: O=C(CCl)NC[C@@H](O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: CO
Solvent: O
Product: O=C1CO[C@@H](CO)CN1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
(R)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (1.31 g, 8.20 mmol) in tert-amyl alcohol (34 mL) was added dropwise over 2 h to a stirred solution of potassium tert-butoxide (2.30 g, 20.6 mmol) in tert-amyl alcohol (16 mL) at room temperature under nitrogen. After 1 hr, MeOH (8 mL) and water (0.5 mL) were added and the reaction mixture was stirred for an additional 20 min. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (2/8) to give the title compound as a white solid (0.59 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[CH:19]1([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]([C:4]1[N:23]=[C:22]([CH:19]2[CH2:21][CH2:20]2)[S:24][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.07 min; [M+H]+=328.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][CH2:24][O:25]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1.O[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47]>>[C:46]([NH:45][CH2:44][CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[O:25][CH2:24][CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]1)(=[O:48])[CH3:47]
Reactant: CC(=O)NCCc1ccccc1O
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.24 g of tertbutyl 4-(4-methoxyphenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.17 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as an orange oil. Rf=0.50 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.85.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (3.4 g) in dry dichloromethane is treated with bromotrimethylsilane (1.5 ml) under argon at room temperature. After 3 hours the dichloromethane and excess bromotrimethylsilane are removed in vacuo and the residue taken up in water and ethyl acetate and stirred for 5 minutes. The layers are separated and the organic phase is washed with brine and dried (MgSO4). The solvent is stripped yielding 3.3 g of the title compound as a foam.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[N:27]=[C:28]([CH3:32])[N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH2:35]1CCN2C(=NCCC2)C[CH2:36]1.C(I)C.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:35]([N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([O:8][Si:9]([CH2:14][CH3:15])([CH2:10][CH3:11])[CH2:12][CH3:13])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:33])[F:34])[CH2:21][CH2:20]1)[S:23]([C:26]1[N:27]=[C:28]([CH3:32])[N:29]([CH3:31])[CH:30]=1)(=[O:25])=[O:24])[CH3:36]
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2cn(C)c(C)n2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)CC1)S(=O)(=O)c1cn(C)c(C)n1
Reaction time: 0.25 h

Procedure:
A solution of 150 mg (0.28 mmol) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid [4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide (example 9.1) in 1 mL of DMF was treated with 0.66 mL (0.44 mmol) of DBU, stirred for 15 min and treated with 0.9 mL (0.58 mmol) of ethyliodide. The mixture was stirred at 60° C. for 4 hrs and distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 150 mg (95%) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a light yellow liquid, MS: 566 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=C(C(O)=O)[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[CH:43]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[C@@H:51]([CH3:62])[CH2:50]3)[CH:45]=[CH:46][CH:47]=2)[CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:87]([OH:93])([C:89](F)(F)F)=O>ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[C:89]([C:87]([NH:34][CH2:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][NH:52][C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[CH:37]=4)=[O:93])[N:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccn3)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccnc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (30 mg, 0.066 mmol) was added 1,1-dimethylethyl (2S)-4-({3-[4-(aminomethyl)-2-pyridinyl]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (26.3 mg, 0.066 mmol), followed by HBTU (30.2 mg, 0.080 mmol) and TEA (18.48 μl, 0.133 mmol) in dichloromethane (DCM) (663 μL) to give a reaction mixture which was stirred at room temperature overnight. Then the reaction was quenched with H2O (1 drop) and the solvent was removed using a Glas-Col. The crude product was redissolved in MeOH/DMSO (1/1) and purified by Gilson HPLC (acidic condition). Product fractions were evaporated by GeneVac EZ-2 evaporator. To this material was added TFA (0.102 mL, 1.33 mmol) in dichloromethane (0.2 mL) and it was placed in the Glas-Col evaporator overnight. It was redissolved in MeOH/DMSO and purified using a Gilson HPLC (acidic condition). Product fractions were evaporated by GeneVac EZ-2 evaporator, basified by cartridge to afford 19.1 mg (37%) of the title compound. LC-MS m/z 731 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CC1

Procedure:
The title compound, white solid (73 mg, 74%), MS (ISP) m/z=395.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and cyclopropanecarboxylic acid.