Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: OCc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(CO)cc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (0.28 g), 4-hydroxymethylphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.28 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.21 g, m.p. 110°-114° C., {α]D25 +16 2° (c 1.0, CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH2:22][O:23][CH2:24][C@@H:25]1[CH2:29][C@@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][N:26]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:22]\[O:23][CH2:24][C@@H:25]2[CH2:29][C@@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][N:26]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 58.8 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (183 mg, 0.5 mmol), (2S,4R)-tert-butyl 2-(aminooxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate (692 mg, 2.0 mmol), Hg(OAc)2 (320 mg, 1.0 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to r.t., filtered through celite and purified to afford (2S,4R)-tert-butyl 2-(((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5-(6H)-ylidene)aminooxy)methyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate (200 mg, 50%) as off white solid. MS (ES) [M+H] calculated for C30H45BrFN6O4Si, 679.24; found 679.20.
Reaction SMILES: [C:1]1([C@H:7]2[O:11][C:10](=[O:12])[NH:9][C@@H:8]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[C:20]C3C=CC=CN=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:28]1[CH:33]=[C:32]([C@@H]2[C@@H](C3C=CC=CC=3)OC(=O)N2)[CH:31]=[CH:30][N:29]=1.C[Si](C#CC1C=NC=CC=1)(C)C>>[C:1]1([C@H:7]2[O:11][C:10](=[O:12])[NH:9][C@@H:8]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[C:20][C:33]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N[C@H](c2ccnc(C#Cc3ccccn3)c2)[C@@H](c2ccccc2)O1
Reactant: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Agent: C[Si](C)(C)C#Cc1cccnc1
Product: O=C1N[C@H](c2ccnc(C#Cc3cccnc3)c2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-5-phenyl-4-(2-(pyridin-2-ylethynyl)pyridin-4-yl)oxazolidin-2-one, starting with (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one and 3-((trimethylsilyl)ethynyl)pyridine. 1H-NMR (CDCl3, 500 MHz) δ 8.82 (bs, 1H), 8.67 (bs, 1H), 7.90 (d, J=7.6, 1H), 7.55 (bs, 1H), 7.30-7.51 (m, 6H), 7.21 (d, J=4.0, 1H), 6.94 (bs, 1H), 5.24 (d, J=7.0, 1H), 4.84 (d, J=7.0, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.9, 151.1, 148.3, 143.9, 139.0, 136.6, 129.8, 129.4, 126.1, 124.6, 120.8, 91.3, 86.9, 85.3, 63.7. Mass spec.: 342.0 (MH)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: -5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of L-hydroxyproline methyl ester hydrochloride (the compound obtained in Reference Example 1-1); 24.37 g, 134 mmol) and triethylamine (41.2 ml, 295 mmol) in methylene chloride (240 ml) was stirred at room temperature for 10 minutes, cooled to -5° C., treated dropwise with a solution of allyl chloroformate (14.9 ml, 140 mmol) in methylene chloride (30 ml). The reaction mixture was stirred at -5° C. for 1 hour, and washed twice with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford the title compound (30.8 g, 100% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[S:15][CH2:16][CH2:17]Cl)[C:5]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6].[I-].[Na+]>CC(=O)CC>[CH2:8]([NH:7][C:5]([C:4]1[CH:12]=[CH:13][C:14]2[S:15][CH2:16][CH2:17][NH:1][C:2]=2[CH:3]=1)=[O:6])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CNC(=O)c1ccc(SCCCl)c(N)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)CNC(=O)c1ccc2c(c1)NCCS2
Temperature: 70 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a solution of 3-amino-4-(2-chloroethylthio)-N-isobutylbenzamide (2.386 g, 8.32 mmol) in 2-butanone (150 ml) was added sodium iodide (1.247 g, 8.32 mmol). The reaction was heated to 70° C. and stirred for 24 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was concentrated in vacuo and purified by flash column chromatography [gradient elution (hexanes with 5-50% EtOAc)] to provide N-isobutyl-3,4-dihydro-2H-benzo[b][1,4]-thiazine-6-carboxamide (1.61 g, 6.43 mmol) as an off white solid. The total overall yield for steps 2-5 was 77%. LCMS (+ESI) m/z=523.34 [2M+Na]+.
Reaction SMILES: C([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])(OCC1C=CC=CC=1)=O.[ClH:17].[CH3:18][NH:19][CH3:20].CN1CCOCC1>>[ClH:17].[CH3:18][N:19]([CH3:20])[C:14](=[O:16])[C@@H:12]([CH3:13])[NH2:11]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNC
Agent: Cl
Solvent: CN1CCOCC1
Product: C[C@@H](N)C(=O)N(C)C

Procedure:
N1,N1-dimethyl-D-alaninamide, hydrochloride salt was prepared in a manner similar to Example 69, utilizing N-CBZ-D-alanine in place of N-CBZ-glycine, utilizing dimethylamine, hydrochloride salt in place of pyrrolidine, and using 3 equivalents of NMM.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:13])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[N:14]#[C:15]N>>[C:15]([N:13]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[O:9][CH2:10][CH2:11][CH3:12])#[N:14]
Reactant: CCCOC(=N)c1cncc(C)c1
Reactant: N#CN
Product: CCCOC(=NC#N)c1cncc(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To propyl 5-methyl-3-pyridinecarboximidate was then added an aqueous solution (100 ml) of cyanamide (1.42 g, 33.8 mmol), Na2HPO4 (2.40 g, 16.9 mmol) and NaH2PO4 ·2H2O (10.56 g, 67.7 mmol). The mixture was stirred at room temperature for 5 hours and extracted with chloroform (100 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-methyl-3-pyridinecarboximidate (2.54 g). IR (neat) cm-1 : 2200, 1610, 1320, 730.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:15]=1.[NH3:26]>CO>[NH2:18][CH2:17][CH2:16][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:26])[C:5]=2[N:15]=[C:2]1[NH2:1]
Reactant: CC(C)(C)OC(=O)NCCn1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: NCCn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
tert-Butyl 2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (3.5 g, 9.7 mmol) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. overnight. The volatiles were removed under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 1.5:28.5:70) to provide 840 mg of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a dark grey solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:39][C:35]1[CH:34]=[C:33]([C:11]2[N:10]=[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]3=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[CH:17][N:13]3[N:12]=2)[CH:38]=[N:37][CH:36]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Nc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 110 °C
Yield: 8.5 %

Procedure:
N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.597 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (0.263 g, 1.20 mmol, commercial) were dissolved in dioxane (10 mL) and water (2 mL). To the above solution was added K2CO3 (0.248 g, 1.79 mmol) and the reaction mixture was degassed with nitrogen for 15 minutes then PdCl2(dppf)-CH2Cl2 (0.0490 g, 0.0600 mmol) was added. The resulting reaction mixture was degassed for 20 minutes and heated to reflux at 110° C. for 14 h. The reaction mixture was allowed to cool, concentrated under reduced pressure and diluted with CH2Cl2 (10 mL). The resulting solid was filtered through a CELITE® bed and the filtrate dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-62 as described in general methods) to afford 2-(5-aminopyridin-3-yl)-N-benzyl-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (20.0 mg, 8.53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.81 (d, J=6.0 Hz, 2H), 5.46 (s, 2H), 6.54 (t, J=6.0 Hz, 1H), 6.78 (d, J=2.8 Hz, 1H), 7.26-7.54 (m, 10H), 7.75 (dd, J=2.0 Hz, J=2.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H). LCMS Condition B-47: retention time 2.20 min, [M+1]=393.2. HPLC Condition B-63: retention time 24.18 min, Purity 97.00%.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([O:35][CH3:36])[N:21]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)n1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(Cl)n1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 10.1 mmol, 3.4 g), 2-Chloro-6-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq, 10.1 mmol, 2.9 g), Na2CO3 (2 eq, 19 mmol, 2 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 224 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=343/345.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C1C=CC=CC=1.C([C@@H]([C@H](C(OCC)=O)O)O)(OCC)=O.[C:26]1([C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:38][C@@H:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](O)c1ccccc1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A dispersion of 0.43 g (11.3 mmol) of sodium borohydride in THF (20 ml) was cooled in a cryostat at -20° C., 1.38 g (11.3 mmol) of benzoic acid was added with stirring, and the mixture was stirred for two to three minutes. A solution of diethyl L-(+)-tartrate in THF (10 ml) was then added, the mixture was stirred for five minutes, a solution of 5 g (2.8 mmol) of ethyl phenyl-glyoxylate in THF (2 ml) was further added over a period of one to two minutes, and stirring was continued for one hour. The reaction mixgture was treated in the same manner as described in Example 1, giving 0.43 g of ethyl (S)-(+)-2-hydroxy-2-phenylacetate, having specific rotation [α]D18 of +17.6° (cl. 18, CHCl3). The synthesis yield was 85% and the optical yield was 15% e.e. (see Reference 7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[C:33]([N:35]=[C:36]=[O:37])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39].C1COCC1>>[Cl:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:33]2[CH:32]=[CH:31][C:30]([O:38][CH3:39])=[C:29]([Cl:28])[CH:34]=2)=[O:37])=[CH:7][C:6]=1[C:8]1[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: COc1ccc(N=C=O)cc1Cl
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(-c3cc4cnc(NCCN(C)C)nc4n(OC)c3=O)c2)cc1Cl
Temperature: 25 °C
Yield: 56 %

Procedure:
In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin -7(8H)-one (165 μmol). A solution of 2-chloro-4-isocyanato-1-methoxybenzene in THF (2 mL, 129 mmol) was added, and the mixture was stirred at room temperature over night. The solvent was allowed to evaporate over night, and the remaining solid was dissolved in DMSO, transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 1-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(3-chloro-4-methoxyphenyl)urea as a solid (56%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1.CO.O.[SH-].[Na+]>O>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(-c3cccc([N+](=O)[O-])c3)nc2n1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2oc(-c3cccc(N)c3)nc2n1
Yield: 45.3 %

Procedure:
5-Methyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (50 mg, 0.196 mmol) was mixed with 6 mL of MeOH along with 2 mL of water and 66 mg of sodium hydrosulfide hydrate. The reaction mixture was stirred under reflux for 2 hours. It was then concentrated and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 20 mg of 3-(5-methyl-oxazolo[4,5-b]pyridin -2-yl)-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:44])=[CH:25][C:24]=2[OH:30])[N:10]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a mixture of 37.9 g (0.100 mol) of 2,4-bis(2′,4′-dimethylphenyl)-6-(2′,4′-dihydroxyphenyl)-1,3,5-triazine, 14.5 g ( 0.105 mol) of potassium carbonate (Fluka, 99.0%) in 250 ml of N,N-dimethylformamide (DMF, Fluka, 99.5%) there are added dropwise with stirring at 80° C. 19.0 g (0.105 mol) of ethyl 2-bromopropionate (Fluka, 98%). The mixture is held at 80° C. for 1 h, then poured into 4 l of cold water and subjected to extraction with 2 l of ethyl acetate. The organic phase is filtered and washed with 2×500 ml of water and dried (MgSO4). Removal of the solvent and drying at 60° C./60 mmHg/24 h give 39.0 g of 2,4-bis(2′,4′-dimethylphenyl)-6-(2′-hydroxy-4′-(1″-(ethoxycarbonyl)ethoxy)phenyl)-1,3,5-triazine as pale yellow crystals of m.p. 120-122° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7](=[O:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=1.O1CCOCC1.[Cl-].[Li+]>[Cu]I.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>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=4)[S:6][C:5]=3[C:7](=[O:17])[CH2:8]2)=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)c2cc(Br)sc21
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2cc3c(s2)C(=O)CC3c2ccc(Cl)cc2)ccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.046 g, 0.141 mmol) and N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.063 g, 0.211 mmol) in anhydrous 1,4-dioxane (2.00 mL, 25.63 mmol) was degassed for 10 minutes. Lithium chloride (0.018 g, 0.42 mmol) and copper(I) iodide (0.008 g, 0.043 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (2.00 mL) and extracted with EtOAc (2.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using an ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.044 g, 78%) as a yellow oil. LC/MS (AA) ES+ 383, 385. 1H NMR (dmso-d6, 400 MHz): δ 10.68 (s, 1H), 8.40 (s, 1H), 8.36 (d, 1H), 7.66 (s, 1H), 7.50 (dd, 1H), 7.42-7.40 (m, 2H), 7.30-7.28 (m, 2H), 4.72 (dd, 1H), 3.48 (dd, 1H), 2.82 (dd, 1H), 2.11 (s, 3H).
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-])=[O:17])=[CH:10][N:9]=1.C[O-].[Li+].O1CCCC1.C(Cl)[Cl:31]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]([Cl:31])=[N:16][OH:17])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])CCc1ccc(Oc2cccc(F)c2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a methanol (20 mL) solution of 2-(3-fluoro-phenoxy)-5-(2-nitro-ethyl)-pyridine (1.96 g, 7.47 mmol) described in Manufacturing Example 71-1-3 was added lithium methoxide (567 mg, 14.9 mmol), which was stirred for 35 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. Titanium (IV) tetrachloride (1.81 mL, 16.4 mmol) was added under nitrogen atmosphere to a tetrahydrofuran (20 mL) and methylene chloride (20 mL) suspension of the residue, and stirred for 1 hour 15 minutes at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.1 g, quant.). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].F[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]([N+:21]([O-])=O)[C:9]=1[NH2:24].O.[OH-].[Na+]>C1COCC1>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:13]3[CH:8]=[C:9]([NH2:24])[C:10]([NH2:21])=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)[CH2:10][CH2:9][CH2:8][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame dried 500 mL three-necked round bottom flask purged with N2 was charged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). The resulting suspension was cooled to 0° C. and a suspension of t-butyl ester 1 (10.0 g, 29.0 mmol) in dry THF (60 mL) was slowly added while keeping the internal reaction temperature under 5° C. The reaction was stirred at 0° C. for 30 min then at rt for 30 min. After the reaction was judged complete, the mixture was treated with successive dropwise addition of water (2.3 mL), 10% NaOH (253 mL), and water (7.2 mL). The resulting suspension was filtered through Celite, washed with ethyl acetate and methanol, and the collected organics concentrated. The crude product was absorbed onto silica gel and purified by flash chromatography (97: 3 CH2Cl2/MeOH) to give 2 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.5 Hz, 1H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1H), 6.92 (d, J=9.35 Hz, 1H), 6.75 (m, 2H), 4.68 (s, 2H), 3.07 (d, J=5.23 Hz, 3H).