Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[N:10]1([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-n2cccn2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (1.0 g, 7.2 mmol) and pyrazole (2.4 g, 35.9 mmol) were dissolved in DMF (10 ml), and potassium carbonate (3.0 g, 21.7 mmol) was added thereto. The mixture was stirred at 100° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.98 g, 80%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOC(C)=O>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:10]([CH2:9][CH2:8][O:7][C:6]1[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=1)[S:11]([CH3:14])(=[O:12])=[O:13])[CH3:30]
Reactant: CS(=O)(=O)NCCOc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of NaH (60% in oil, 338 mg, 8.45 mmol) in DMF (23 mL) was cooled to 0° C. followed by addition of N-[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonamide (2.0 g, 7.04 mmol). The reaction was stirred at room temperature for 0.5 h and was cooled to 0° C. followed by addition of ethyl 7-bromoheptanoate (2.0 g, 8.45 mmol). The reaction was heated at 65° C. for 3 h and was cooled to room temperature. EtOAc was added and the organic solution was washed consecutively with 1N HCl, water, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (4:1 hexanes:EtOAc) provided the title compound (2.84 g). 1HNMR (400 MHz, CDCl3) δ6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56 (t, 2H), 3.22 (t, 2H), 2.86 (s, 3H), 2.26 (t, 2H), 1.60 (m, 4H), 1.32 (m, 4H), 1.22 (t, 3H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]([CH2:25][C:26]#[CH:27])[NH2:24])=[N:15][O:16][C:12]=2[CH:11]=1>CO>[ClH:9].[O:16]1[C:12]2[CH:11]=[CH:10][CH:29]=[CH:28][C:13]=2[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C@H:23]([CH2:25][CH:26]=[CH2:27])[NH2:24])=[N:15]1
Reactant: C#CCC(N)c1ccccc1-c1noc2cc(Cl)ccc12
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: C=CC[C@H](N)c1ccccc1-c1noc2ccccc12
Product: Cl

Procedure:
(−)-2-(6-chloro-1,2-benzisoxazol-3-yl)-a-2-propynyl-benzenemethanamine (E)-butenedioate (2:1 salt), melting at 198-202° C., a (c=0.5 in methanol) −19.7,
Reaction SMILES: [O:1]1[CH2:5]CCC1.[NH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>C(N(CC)CC)C>[CH3:16][Si:17]([CH3:20])([CH3:19])[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:6]=[C:5]=[O:1])=[CH:10][CH:11]=1
Reactant: NCCc1ccc(O)cc1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(CCN=C=O)cc1
Reaction time: 0.5 h

Procedure:
Into a 250 ml, three-necked flask fitted with a reflux condenser, gas inlet tube and magnetic stirrer and kept under a positive pressure of any dry nitrogen, there was charged 100 ml of dry tetrahydrofuran, 1.4g (0.01 mol) of tyramine and 5.0 ml of triethylamine. 3.0 ml of trimethylchlorosilane was then added at ambient temperature, dropwise and with stirring over a period of 30 minutes. Carbon dioxide was thereafer slowly bubbled into the reaction mixture, via a syringe needle for four hours while the mixture was allowed to reflux for the same period. Introduction of carbon dioxide was then terminated, and 1.5 ml of silicon tetrachloride was added slowly using a syringe. After 30 minutes of additional heating, the reaction mixture was allowed to cool, and triethylamine hydrochloride was removed by filtration. The solvent was then removed at 35° C in vacuo (12 torr), and the resulting oil distilled at 88°-90° C. (0.05 torr) to give a 2-(4'-trimethylsiloxyphenyl)ethyl isocyanate as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:24]1([CH2:30][N:31]=[C:32]=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([CH2:30][NH:31][C:32](=[O:33])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:9]=[CH:10]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc2c(ccn2Cc2ccncc2)c1
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Oc1ccc2c(ccn2Cc2ccncc2)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-pyridinylmethyl)-1H-indol-5-ol (2.2 g) in 50 ml tetrahydrofuran, was added milled K2CO3 (1.4 g) followed by phenylmethyl isocyanate (1.2 ml). After stirring at ambient temperature for twenty hours, the mixture was filtered, and the filtrate evaporated to an oil, (18 3.5 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and evaporated to yield 2.8 g of 1-(4-pyridinylmethyl)-1H-indol-5-yl phenylmethylcarbamate, m.p. 112°-114° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[O:8][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([F:22])=[C:15]([Cl:14])[CH:16]=2)=[O:13])[O:8][N:7]=1
Reactant: O=C(O)c1cc(OCCCBr)no1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCBr)no1
Temperature: 0 °C
Yield: 387.4 %

Procedure:
A solution of 3-(3-bromopropoxy)isoxazole-5-carboxylic acid (130 mg, 0.054 mmol) and 3-chloro-4-fluoroaniline (78 mg, 0.054 mmol) in pyridine (2.0 mL) was stirred at room temperature until totally dissolved. The solution was cooled to −30° C. (acetonitrile/ice) and phosphoryl chloride (240 μL, 2.6 mmol) was added dropwise. The mixture was stirred for 1 h in the ice bath. The mixture was diluted with toluene before evaporation in vacuo. The crude was purified by reverse phase chromatography to give the desired product (79 mg, 39%). MF=C13H12BrClFN2O3; LCMS calculated for C13H12BrClFN2O3 (M+H)+: m/z=377.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:12]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH2:10])=[C:12]([C:27](=[O:28])[NH:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:13]=2)=[CH:18][CH:19]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Dichloromethane (200 mL) and diisopropylethylamine (2 g, 17.16 mmol) were added to the product of step (vii) (4 g, 11.46 mmol). The resulting solution was cooled to 0° C. and MsCl (2 g, 17.16 mmol) added dropwise. When the addition was completed, the resulting solution was stirred at 0° C. for 10 minutes and at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (viii) as a yellow brown solid (4.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[O:11]CCC2C=CC(Br)=CC=2C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][CH3:31])[C:27]([CH2:32][CH2:33][OH:34])=[C:26]([CH2:35][CH3:36])[CH:25]=1.N(C1C=C(C=CC=1)C#N)=C=O>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[O:34][CH2:33][CH2:32][C:27]2[C:26]([CH2:35][CH3:36])=[CH:25][C:24]([Br:23])=[CH:29][C:28]=2[CH2:30][CH3:31])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: CCc1cc(Br)cc(CC)c1CCO
Agent: N#Cc1cccc(N=C=O)c1
Product: CCc1cc(Br)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 86 %

Procedure:
Using a procedure analogous to that used to prepare 30C, 37C (280 mg, 1.95 mmol) was reacted with 3-isocyanatobenzonitrile to yield 37D (670 mg, 86%) as an yellow oil. 1H NMR (400 MHz, CD3OD) δ ppm 1.22 (t, J=7.58 Hz, 6 H) 2.73 (q, J=7.58 Hz, 4 H) 3.06 (t, J=8.1 Hz, 2 H) 4.21 (t, J=8.1 Hz, 2H) 7.19 (s, 2 H) 7.32-7.39 (m, 1 H) 7.40-7.50 (m, J=8.08, 8.08 Hz, 1 H) 7.66 (d, J=8.34 Hz, 1 H) 7.86 (s, 1 H).
Reaction SMILES: [C:1]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:22](O)(=O)(=O)=O>C(O)(=O)C.[Pd].C(OCC)(=O)C>[ClH:22].[CH2:1]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCCCCCCC(=O)c1c[nH]c2cc(C(=O)O)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCC1CNc2cc(C(=O)O)ccc21
Product: Cl

Procedure:
3-(n-Octanoyl)indole-6-carboxylic acid (39.4 g) in glacial acetic acid (860 ml), containing perchloric acid (37 ml, of strength 70% w/v), was hydrogenated over palladium on charcoal (17 g of 5% w/w) at atmospheric pressure and at a temperature between 80°-90° C. The catalyst was removed by hot filtration through diatomaceous earth and on cooling a solid separated which was collected. The solid was washed with diethyl ether (2×100 ml) and was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous solution of sodium carbonate (2×100 ml of strength 2N) and was dried over magnesium sulphate and on evaporation in vacuo gave an off-white solid. The solid was dissolved in ethyl acetate (200 ml) and hydrogen chloride gas was bubbled through the solution. The resulting solid was collected and was washed with diethyl ether (2×200 ml) to give (RS)-3-(n-octyl)indoline-6-carboxylic acid hydrochloride (14.5 g), in the form of an off-white solid, m.p. 233°-234° C. with decomposition.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH3:51])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl.C1COCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH3:51])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CN[C@@H](C)CN1CC(O)C1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 19 %

Procedure:
DIPEA (0.217 mL, 1.25 mmol) was added to a stirred suspension of 4-bromobenzoic acid (0.075 g, 0.37 mmol) and TBTU (0.120 g, 0.37 mmol) in DCM (2 mL) at rt. The suspension was stirred for 20 min before it was cooled on an ice-bath. A solution of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06 g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath was removed and the reaction was stirred at rt over night. DCM (3 mL) was added and the mixture was washed with NaHCO3 (8% aq., 3 mL). The aqueous layer was extracted with DCM (2×3 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (23 mg, 17%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 1.01-1.11, 2.17-2.24, 2.33-2.38, 2.45-2.77, 3.15-3.56, 4.03-4.20, 4.44-4.53, 5.18-5.28, 7.27-7.34, 7.59-7.66. Some signals overlap with solvent. HRMS (M+H)+: calculated 327.0708. found 327.0722.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](OCC)=[O:26])=[N:4][C:5]([NH:17][C@H:18]2[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20][CH2:19]2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].O[C@@H]1CC[C@H]([NH:37]C2N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC3C=CC=CC=3OC)N=2)CC1.[CH2:61]([OH:63])C>[Pd]>[OH:24][C@@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:61](=[O:63])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:37])=[O:26])[N:4]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 5-amino-2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenyl-amino)-5-nitropyrimidine-4-carboxylate (0.340 g, 0.788 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.070 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using Biotage chromatography (5% methanol in ethyl acetate) to afford the title compound (0.272 g, 70%). MS (ESI) m/z 402.4 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:27])=[O:24]
Reactant: COC(=O)Cc1cccc(OCC(C)=O)c1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1cccc(OCC(C)NCC(O)c2cccc(Cl)c2)c1
Yield: 58.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.11 g of methyl 3-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 17), 70 ml of benzene, 60 ml of absolute methanol and 2.45 g of sodium cyanoborohydride, 2.57 g of the title compound were obtained having an Rf=0.38 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:2]([C@@H:3]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Yield: 165.5 %

Procedure:
Methyl 2(S)-amino-3-cyclohexylpropionate hydrochloride (150 g) was dissolved in N,N-dimethylformamide (1200 ml). Thereto was added pulverized potassium carbonate (330.7 g), and benzyl bromide (254.6 g) was dropwise added to the obtained suspension while stirring. After the dropwise addition, the inner temperature was raised to 50° C., and the reaction mixture was stirred at said temperature for 9 hours. The reaction mixture was cooled and filtered. Water (600 ml) and diisopropyl ether (600 ml) were added to the filtrate for partition, and the organic layer was separated. The water layer was re-extracted with diisopropyl ether (300 ml), and the combined organic layer was washed with 5% hydrochloric acid (600 ml), 5% aqueous sodium hydrogencarbonate (600 ml), and 25% aqueous sodium chloride sequentially and dried over magnesium sulfate. The solvent was distilled away to give 204.6 g of methyl 2(S)-(N,N-dibenzylamino)-3-cyclohexylpropionate.
Reaction SMILES: CN(C=O)C.O=[C:7]1[NH:12][C:11]([CH2:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[N:10][C:9]2[S:23][C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=3[C:8]1=2.S(Cl)([Cl:32])=O>>[Cl:32][C:7]1[C:8]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:9]=2[N:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCOC(=O)COCc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Solvent: CN(C)C=O
Product: CCCCOC(=O)COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Reaction time: 2 h

Procedure:
1.7 g of sodium hydride (50% suspension) are added to a solution of 5.0 g of “AB” and 2.8 g of butyl glycolate in 100 ml of THF, and the mixture is refluxed for 3 hours. The solvent is removed, and the mixture is subjected to conventional work-up, giving 5.0 g of butyl (4-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate (“AC”). 1 ml of DMF is added to a solution of 5.0 g of “AC” in 50 ml of thionyl chloride, and the mixture is stirred at 45° for 2 hours. After the solvent has been removed, the mixture is subjected to conventional work-up, giving 4.5 g of butyl (4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate (“AD”).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:55]1[C:63]2[C:58](=[C:59]([CH2:64][NH2:65])[CH:60]=[CH:61][CH:62]=2)[CH:57]=[N:56]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]3[C:58]=2[CH:57]=[N:56][NH:55]3)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: NCc1cccc2[nH]ncc12
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.9 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (200 mg, 0.91 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.38 mL, 2.73 mmol), HBTU (0.52 g, 1.37 mmol), HOBT (0.147 mg, 1.09 mmol), and C-(1H-Indazol-4-yl)-methylamine (146 mg, 1.0 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-70% EtOAc in hexane to afford the desired product (0.073 g, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26].O[O:28][S:29]([O-:31])=O.[K+].O1CCC[CH2:34]1>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:29]([CH3:34])(=[O:31])=[O:28])=[N:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26]
Reactant: O=S([O-])OO
Reactant: CSc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1ccccc1Cl)C2
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(2-chlorophenyl)-7-methylthio-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2 g) in 20 mL of tetrahydrofuran at 0° C. was added a solution of 8.1 g of Oxone® in 24 mL of water. The mixture was stirred for 5 hours at room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and evaporated to give 2 g of 3-(2-chlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, m.p. 185.8-186.3° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([N:20]3[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]3)[CH:28]=2)[C:11]=1[CH3:12]
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCN(C)CC3)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.0 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.61 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.0 mmol) in toluene (4.0 mL) at 100° C. for 22 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=389.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[S:27].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: Fc1ccccc1N=C=S
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.48g, 0.03 mol), 2fluorophenyl isothiocyanate (5.0 g, 0.033 mol) and toluene (30 ml) was heated under reflux for 1.5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 7.9 g (59 %), m.p. 145°-147 ° C.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:23](Br)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:17]1([CH:23]([NH:15][C:13]2[CH:14]=[C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:16][C:10]3=[N:11][CH:12]=2)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Solvent: CN(C)C=O
Product: CC(Nc1cnc2[nH]c(-c3ccccc3)nc2c1)c1ccccc1
Reaction time: 18 h

Procedure:
100 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine from ex. b) were dissolved in 1 mL dry dimethylformamide (DMF) and 92 mg 1-phenylethyl bromide were added at room temperature. The mixture was stirred for 18 hours (hrs), the DMF was removed under vacuum and the residue purified by chromatography on silica eluting stepwise first with dichloromethane, then dichloromethane/methanol (60:1), then dichloromethane/methanol/ammonia (60:1:0,2). Product containing fractions were pooled and further purified by preparative HPLC-MS.