Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:3])[CH3:4]
Reactant: CCCCCCC=O
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.66 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 5.0 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, 15.2 g of heptaldehyde, 2.52 g of sodium cyanoborohydride and 53 ml of acetonitrile. The mixture is stirred at room temperature for 2 hours, cooled, acidified to pH=1 with concentrated hydrochloric acid and evaporated to remove the acetonitrile. The residue is diluted with water, the solution washed with diethyl ether, basified to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with chloroform. The extract is dried, evaporated and the residue crystallized from ethanol-water (5:2) to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 102°-104°.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[NH:33][C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[N:33]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:24])([CH3:25])[O:18]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2Cc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-2-{(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl}-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide (170 mg, 0.37 mmol) and 4-chlorobenzaldehyde (104 mg, 0.74 mmol) and acetic acid (44 mg, 41 μL, 0.74 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 30 minutes and then treated with sodium triacetoxyborohydride (196 mg, 0.93 mmol). After 24 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phase was collected, dried over MgSO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-{(1R,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide as a pale yellow oil which was used immediately in the next step; m/z for C32H51BClN3O4 expected 587.4. found 589.7 (M+H(37Cl))+, 588.0 (M+H(35Cl))+,
Reaction SMILES: Br[C:2]1C(F)=C2C(=CC=1)OC1=NC=C(I)C=C1C2=O.[Br:19][C:20]1[CH:21]=[C:22]2[C:32](=[CH:33][C:34]=1[F:35])[O:31][C:25]1=[N:26][CH:27]=[C:28]([I:30])[CH:29]=[C:24]1[C:23]2=O.C[Mg]Cl.BrC1C(F)=C2C(=CC=1)OC1=NC=C(I)C=C1C2=C>O1CCOCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:32](=[CH:33][C:34]=1[F:35])[O:31][C:25]1=[N:26][CH:27]=[C:28]([I:30])[CH:29]=[C:24]1[C:23]2=[CH2:2]
Reactant: O=c1c2cc(Br)c(F)cc2oc2ncc(I)cc12
Reactant: O=c1c2cc(I)cnc2oc2ccc(Br)c(F)c12
Agent: C=C1c2cc(I)cnc2Oc2ccc(Br)c(F)c21
Agent: C[Mg]Cl
Solvent: C1COCCO1
Product: C=C1c2cc(Br)c(F)cc2Oc2ncc(I)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
A suspension of 7-bromo-6-fluoro-3-iodo-5H-chromeno[2,3-b]pyridin-5-one and 7-bromo-8-fluoro-3-iodo-5H-chromeno[2,3-b]pyridin-5-one (1:4 mixture) (76 g, 182 mmol) in 1 L dioxane was placed under argon and was heated with a heat gun until it became a homogenous solution. The solution was allowed to cool to room temperature and stir 72 hours. The reaction mixture was then cooled to −10° C. and was treated with methylmagnesium chloride (106 mL, 319 mmol) dropwise with stirring over 30 min. After stirring for an additional 60 min, the reaction mixture was quenched with MeOH (25 mL). Water (250 mL) was added, followed by concentrated NH4Cl solution (250 mL). The reaction mixture was concentrated in vacuo to remove most of the organics. The remaining aqueous solution was extracted with EtOAc (3×500 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude residue was taken up in ˜300 mL CH2Cl2 and was again concentrated. This process was repeated 3×. The crude black solid was triturated with MeOH and was again dried to provide a 1:10 mixture of 7-bromo-6-fluoro-3-iodo-5-methylene-5H-chromeno[2,3-b]pyridine and 7-bromo-8-fluoro-3-iodo-5-methylene-5H-chromeno[2,3-b]pyridine (59.200 g, 142 mmol, 78% yield). This material was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CO)cc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(COS(C)(=O)=O)cc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-6-methyl-pyridin-4-yl)-methanol (0.300 g, 1.48 mmol) in dichloromethane (2.0 mL) was added DIPEA (776 μL, 4.45 mmol). The resulting mixture was cooled to 0° C. and methanesulfonyl chloride (120 μL, 1.56 mmol) was added. After 1 hour, the reaction mixture was diluted CH2Cl2 (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford methanesulfonic acid 2-bromo-6-methyl-pyridin-4-ylmethyl ester as crude product which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3Cl)CCC2)cc1
Yield: 89.8 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 280 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methythio)benzene (Example 1, Step 2) was reacted with 350 mg (1.9 mmol) of 2,4-dichlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 280 mg of 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) δ 2.10 (m, J=7 Hz, 2H), 2.41 (s, 3H), 2.81 (t, J=8 Hz, 4H), 2.92 (m, J=8 Hz, 2H), 6.95-7.21 (m, 6H), 7.40 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (2.66 g, 13.6 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (2.26 mL, 15 mmol) and sodium bicarbonate (2.29 g, 27.2 mmol) in EtOH (35 mL) is heated to 85° C. for 1 hour and poured into water (100 mL). The solid precipitate is collected by filtration and dissolved in hot EtOH (75 mL). After cooling overnight the crystals that formed are collected by filtration and dried to afford (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (3.43 g, 72%) as a solid.
Reaction SMILES: C1(C)C=CC=CC=1.[OH:8][N:9]=[C:10]1[CH2:18][C@@H:17]2[C@@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:11]1.[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][C:25]#[N:26]>O>[C:25]([CH2:24][CH2:23][CH2:22][O:8][N:9]=[C:10]1[CH2:11][C@@H:12]2[C@@H:17]([CH2:16][CH:15]=[CH:14][CH2:13]2)[CH2:18]1)#[N:26]
Reactant: ON=C1C[C@H]2CC=CC[C@H]2C1
Reactant: N#CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCCCON=C1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (20 ml) of 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene (1 g), was added sodium hydride (50% mineral oil dispersion, 330 mg), and the mixture was stirred for 0.5 hr at room temperature. After addition of γ-chlorobutyronitrile (5 g) to the mixture, stirring was continued for 2 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over Na2SO4 and concentrated to give an oil. This material was chromatographed on silica gel to give 8-(3'-cyanopropoxy)imino-cis-bicyclo[4,3,0]nona-3-ene as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](=[CH2:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH:2]=1.[CH3:16][NH:17][C:18](=[O:21])[CH2:19][SH:20].[N-]=C=O>ClCCl.C(N(CC)CC)C>[CH3:16][NH:17][C:18]([CH2:19][S:20][CH2:15][CH:9]([C:7](=[O:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:21]
Reactant: C=C(CC(=O)OC)C(=O)c1cccnc1
Reactant: CNC(=O)CS
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CSCC(CC(=O)OC)C(=O)c1cccnc1
Reaction time: 24 h

Procedure:
A solution of methyl 3-(3-pyridylcarbonyl)but-3-enoate in dichloromethane (0.5 mL, 0.1 mM), triethylamine in dichloromethane (0.5 mL, 0.1 mM) and N-methyl-2-sulfanylacetamide (0.6 mL, 0.12 mmol) was stirred for 24 h. PS isocyanate resin (60 mg) was added to the reaction mixture and stirred for 24 h. The solution was filtered and concentrated to give the title compound in quantitative yield, ESMS, (M+1)+311.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:47]=1)[CH:45]=[O:46]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:45]=[O:46])[CH:47]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c(OC)c(OC)c4)cc23)CC1
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane (9.0 mL) and H2O (3.0 mL) was added sodium carbonate (690 mg, 6.51 mmol), and 5-bromo-2,3-bis(methyloxy)benzaldehyde (7.95 mg, 3.25 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.054 mmol). The reaction was then heated in a microwave at 120° C. for 30 min. All solvent was then concentrated and an aqueous wash was performed with EtOAc and H2O. The desired compound then precipitated and was filtered to give 322 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1Oc2ccc(Cl)cc2C1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.204 mol of 5-chloro-2,3-dihydro-2-oxo-3-phenylbenzofuran in 200 ml of anhydrous dimethylformamide is added to a suspension of 0.204 mol of sodium hydride in 100 ml of anhydrous dimethylformamide. The medium is maintained with stirring at room temperature for one hour, 0.224 mol of benzyl bromoacetate is then added slowly and the medium is left for 12 hours at room temperature. The reaction mixture is concentrated under vacuum and hydrolyzed using one liter of water, the aqueous phase extracted with twice 250 ml of benzene, the organic phase dried over anhydrous sodium sulfate and the solvent evaporated off. The residue is washed with isopropyl ether and then filtered. 0.173 mol is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13]
Reactant: Cc1nc2c(Cl)cccc2c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(Cl)cccc2c(Cl)c1C

Procedure:
Prepared according to procedure S using 8-chloro-2,3-dimethylquinolin-4-ol (1.14 g, 5.49 mmol) in POCl3 (7 mL). The resulting precipitate was collected by filtration to have 4,8-dichloro-2,3-dimethylquinoline. Mass Spectrum (ESI) m/e=227 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14](Cl)[CH3:15])[C:10](=[O:12])[CH3:11].[CH3:17][NH:18][CH3:19].C1C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:17])[CH3:15])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Reactant: CNC
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A mixture of 3.0 g (12.5 mmoles) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane and 9.4 ml of a 18 w/v % ethanolic dimethylamine solution is heated at 60° C. for 3 hours in a bomb. The mixture is cooled, admixed with 50 ml of benzene and 10 ml of water, and the organic phase is separated. The aqueous phase is extracted twice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 2.8 g (90.3%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2dimethylamino-propane are obtained as a thick, light yellow oil; b.p.: 140°-141° C./120 Pa. The hydrochloride monohydrate of the base melts at 170°-172° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>CC#N.C(OCC)(=O)C>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(C2CCOCC2)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ncc(C2CCOCC2)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (2.8 g, 15.6 mmol) in CH3CN (52 mL) was added NBS (2.78 g, 15.62 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated sodium carbonate solution, water, brine, dried and concentrated. The crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (3.9 g, 97%) was used for the next step without further purification. LCMS (m/z): 258/260 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 1H), 4.90 (br. s., 2H), 4.14-4.02 (m, 2H), 3.59-3.43 (m, 2H), 2.83 (d, J=5.5 Hz, 1H), 1.91-1.77 (m, 4H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([NH:20][C:19]1[N:15]([CH3:14])[N:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nccc1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1NCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
Benzyl bromide (4.97 g) was added dropwise to a dimethylformamide (15 mL) mixture of 1-methyl-1H-pyrazol-5-amine (2.69 g) and potassium carbonate (4.02 g) at a room temperature, and the obtained solution was then stirred at 70° C. for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1), so as to obtain the title compound (1.54 g) in the form of a light yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH3:37])=[C:6]([C@@:8]2([F:35])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])[C:9]2=[O:34])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH3:37])=[C:6]([C@@:8]2([F:35])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)[N:10]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([OH:27])=[O:26])=[O:22])[C:9]2=[O:34])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)NC(C)(C)C(=O)O)c2cc(C(F)(F)F)ccc21

Procedure:
(S)-tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)-2-methylpropanoate (Ij4): Following general procedure (G), to a solution of XVIII4 (0.24 g, 0.44 mmol) in methylene chloride (5 mL), TFA (0.34 mL, 4.4 mmol) was added. After purification by Prep. HPLC, the title compound was obtained as a white foam solid (140 mg, 65% yield). mp: 107–110° C. MS: 487 (M−H−) (very weak). Anal. Calcd. for C21H17CIF4N2O5: C, 51.60; H, 3.51; N, 5.73. Found: C, 51.29; H, 3.68; N, 5.49. 1H NMR (CDCl3): δ 1.70 (s, 3H), 1.74 (s, 3H), 3.56 (s, 3H), 6.76 (dd, J=8.8 Hz, 1.3 Hz, 1H), 7.27 (m, 1H), 7.36 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.79 (dd, J=2.5 Hz, 0.9 Hz, 1H), 8.59 (s, 1H), 8.78 (s, 1H). IR (KBr, cm−1): 3500, 3337, 1762, 1717, 1532, 1491, 1439, 1320, 1265, 1173, 1132, 1062.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:34][CH:35]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 44.5 %

Procedure:
A solution of 0.38 g of diethyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 4.6 mL of 0.5N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Acetic acid (5 mL) was added, and the resulting white precipitate collected by filtration. The filter cake was washed well with water, methanol, and ether and was dried under reduced pressure to yield 0.15 g (44%) of the title compound, which can be alternatively names as 5,10-dideazaaminopterin; mp >250° C.; NMR (TFA-d1) delta 2.2-2.7 (m, 2H), 2.28; 2.7-2.95 (m, 2H), 5.0-5.2 (m, 1H), 7.35 and 7.85 (AB q, 4H, J=9 Hz), 8.7 (s, 1H), 9.1 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([C:23](OC)=[O:24])[S:21][CH:22]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([C:23]([NH:28][NH2:29])=[O:24])[S:21][CH:22]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Yield: 103.1 %

Procedure:
Methyl 4-(4-(4-cyclopropyl-1H-imidazol-1-yl)picolinamido)thiophene-2-carboxylate (380 mg, 1.0 mmol) was dissolved in ethanol, hydrazine hydrate (0.26 mL, 5.2 mmol) was added, and the reaction was refluxed overnight. The solvent was removed under reduced pressure, and the solids were suspended in acetonitrile and filtered to afford 380 mg of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide as a white solid. M+1=369.1
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][N:27]([CH3:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([N:27]([CH3:26])[CH3:37])=[CH:36][CH:35]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (13.8 mg, 0.052 mmol) in CHCl3 (2 mL) was treated with Et3N (0.021 mL, 0.15 mmol), 4-(dimethylamino)benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was washed with 2 N aqueous NaOH solution (2 mL×2) and brine (2 mL), and dried by filtration through a PTFE membrane using CH2Cl2 (3 mL). Concentration afforded the desired material (compound No. 952) (24.9 mg, quant): The purity was determined by RPLC/MS (91%); ESI/MS m/e 415.0 (M++H, C22H27ClN4O2)