Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][NH:31][CH3:32]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:31]([CH3:32])[CH3:30])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CNC
Product: CN(C)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-dimethylamino-nicotinamide was prepared starting from intermediate E and dimethylamine. MS calcd. for C24H21ClN4O2 [(M+H)+] 433.1, obsd. 432.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([CH2:8][C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH:17]=[C:16]([CH3:18])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[H-].[Na+].I[CH3:27].Cl>CN(C=O)C>[OH:1][CH2:2][C:3]1[C:4]([C:20]([F:22])([F:21])[F:23])=[N:5][N:6]([CH2:8][C:9]2[N:10]([CH3:27])[C:11](=[O:19])[C:12]3[CH:17]=[C:16]([CH3:18])[S:15][C:13]=3[N:14]=2)[CH:7]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(C)c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
2-((4-(Hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (240 mg, 0.697 mmol) was dissolved in DMF (5 mL). NaH (17 mg, 0.708 mmol) was added and the reaction mixture heated at 60° C. for 1 h, then allowed to cool to RT before cooling further with an ice/salt bath to 0° C. Iodomethane (1.14 g, 0.50 mL, 8.03 mmol) was added in one portion and the reaction mixture stirred at RT for 1 h, then allowed to warm to RT, before standing overnight. The reaction mixture was acidified with 2M HCl and extracted into EtOAc (×3). The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by preparative reverse phase HPLC gave the title product as a white solid (76 mg, 0.213 mmol, 31%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])(=[O:20])[NH2:19].O>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[C:25]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:26])/[CH:24]=[CH:23]\[C:22](=[O:27])[NH:21][C:18](=[O:20])[NH2:19]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 49 g of hexadecanol (0.202 moles), 28 g of N-carbamylmaleimide (0.2 moles) and 270 mg of zinc chloride (0.002 moles) in 300 mL of p-dioxane was heated to reflux. After 24 hours, the mixture was cooled to room temperature and 200 mL of H2O was added. The resulting solid was filtered, washed with additional H2O and dried to afford 75 g (97% yield) of hexadecyl maleurate. M.P.: 106°-09° C. (dec.); 1H NMR (CDCl3): δ10.5 (br s, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.4 (br s, 1H), 4.2 (t, 2H), 1.6 (m, 2 H), 1.2 (m, 26H), 0.9 (t, 3H); HPLC (80% CH3CN/H2O, C18): Rt=6.9 minutes.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3cccs3)cc2F)cn1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 2-(2-thienyl)ethylamine (0.217 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.100 g, 18%): TOF MS ES+ 373.1 (M+H)+, HRMS calcd for C15H11N4O2FS 373.1135 (M+H)+, found 373.1150, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=10.3 min. 100% purity.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17].C([O-])([O-])=[O:19].[Ca+2]>COCCOC.O>[Br:1][C:2]1[C:11]([CH2:12][OH:19])=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Yield: 104.4 %

Procedure:
Following a modified procedure of Smith et al.,25 dibromide 36 (1.73 g, 4.80 mmol) was dissolved in 1,2-dimethoxyethane (50.0 mL), and then added to CaCO3 (2.50 g, 25.0 mmol) in H2O (50.0 mL) at room temperature. The reaction was heated under reflux for TIME and then cooled to room temperature. The reaction was extracted with EtOAc (75.0 mL), and the organic layers are washed with brine. The organic layer was dried over MgSO4 and filtered. The resulting pink solid was then purified by flash column chromatography (1:3 EtOAc:hexanes) to provide 37 (1.49 g, 5.01 mmol, 105%) as a pink solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=1.[ClH:25]>O1CCOCC1.CO.CCOC(C)=O>[Cl-:25].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:1])[CH3:24])[CH:4]=3)[NH+:9]=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: Cl
Reactant: CC(=O)Nc1ccc(Nc2ccnc3ccc(N(C)C)cc23)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1ccc2[nH+]ccc(Nc3ccc(N)cc3)c2c1
Product: [Cl-]
Temperature: 20 °C
Yield: 100 %

Procedure:
To a suspension of A5 in 1,4-dioxane (20 mL) was added 1.5 M aq HCl (5 mL) and the reaction mixture was refluxed for 2 h. The reaction mixture was then diluted with MeOH/EtOAc, brought to boil and allowed to cool to 20° C. The resulting precipitate was filtered, washed with EtOAc and dried to give essentially pure A6 as a pale yellow solid (1.20 g, 100%); mp (MeOH/EtOAc) 152-155; 1H NMR [(CD3)2SO] 14.35 (br, 1 H, N+H), 10.50 (br, 2 H, NH2), 8.27 (d, J=6.6 Hz, 1 H, ArH), 7.92 (d, J=9.4 Hz, 1 H, ArH), 7.65 (dd, J=9.5, 2.6 Hz, 1 H, ArH), 7.57 (d, J=2.4 Hz, 1 H, ArH), 7.54 (d, J=8.5 Hz, 2 H, ArH), 7.41 (d, J=8.1 Hz, 2H, ArH), 6.68 (d, J=6.7 Hz, 1 H, ArH), 3.12 (s, 6 H, [N(CH3)2]; APCI+ve 279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.N1CC[C@H:38]([OH:41])C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH2:33][C@H:38]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@H]1CCNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 30 mg, 0.09 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (15.8 mg, 0.181 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 53% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 81% yield). MS (apci) m/z=445.2 (M+H).
Reaction SMILES: Cl.[C:2]12([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([C:48](O)=[O:49])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2([C:48]([N:4]3[CH2:5][CH:6]4[C:2]([C:8]5[C:16]6[C:11](=[N:12][CH:13]=[CH:14][CH:15]=6)[NH:10][CH:9]=5)([CH2:7]4)[CH2:3]3)=[O:49])[CH2:46][CH2:47]2)=[CH:43][CH:44]=1
Reactant: c1cnc2[nH]cc(C34CNCC3C4)c2c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N1CC2CC2(c2c[nH]c3ncccc23)C1)C1(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
3-(3-azabicyclo[3.1.0]hex-1-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (60 mg, 0.3 mmol) was dissolved in DCM (3 ml) and a few drops of DMF, and cooled to 0° C. Then HOBt (38 mg, 0.33 mmol), EDCI (54 mg, 0.33 mmol) were added followed by triethylamine (106 μL) and 1-(4-fluorophenyl)cyclopropanecarboxylic acid (46 mg, 0.3 mmol). The mixture was stirred at RT overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography (DCM/MeOH 97:3) to yield the title compound as a yellow solid (44 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][O:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][O:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CO)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(COS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropane-1,3-diol (79.4 mg, 0.192 mmol) and Et3N (80 uL, 0.574 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (37.4 uL, 0.48 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method J): RT 2.98 min [M+H]+ 570.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC(C)([O-])C.[K+].O1CCCC1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]=[C:29](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:28][N:27]=[C:26]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:25]=2[CH:53]=1>O.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[CH:2]=[N:1][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:29]3[CH2:28][N:27]=[C:26]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:25]=2[CH:53]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)(N1CCOCC1)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1.41 g (0.0125 mole) of ethyl isocyanoacetate, 1.4 g (0.0125 mole) of potassium t-butoxide and 125 ml of tetrahydrofuran was stirred at room temperature for 10 minutes. Following the addition of 5.23 g (0.01 mole) of 7-chloro-5-(2-chlorophenyl)-2-[bis-(morpholino)-phosphinyloxy]-3H-1,4-benzodiazepine stirring was continued for 1/2 hr. The reaction mixture was acidified with glacial acetic acid, diluted with 250 ml of water and extracted with three 100 ml portions of methylene chloride. The methylene chloride extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. The crystalline residue was collected and washed with ether to give product with mp 215°-220°. The material was recrystallized from methylene chloride/ethyl acetate for analysis, mp 225°-228°.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH:26][CH2:27][CH:28]1[O:32][C:31]2=[N:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][N:30]2[CH2:29]1.O>C1COCC1.CN(C=O)C>[O:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:2])[O:26][CH2:27][CH:28]3[O:32][C:31]4=[N:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][N:30]4[CH2:29]3)=[CH:21][CH:20]=2)[CH2:17][CH2:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CO)C2
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)OCC1Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 2 h
Yield: 5.4 %

Procedure:
1,1′-Carbonyldiimidazole (0.44 g, 2.69 mmol) was added to a solution of 4-morpholinoaniline (0.40 g, 2.24 mmol) in THF (4 ml) followed by stirring for 2 hours with cooling on ice-bath. The reaction mixture was filtered and washed with diethyl ether. The filtrate was added to a solution of 2-hydroxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (0.30 g, 1.62 mmol) in DMF (3 ml) with cooling on ice-bath. Then, cuprous chloride (75 mg, 0.76 mmol) was added to the resulting mixture followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/acetone=9/1), and washed with methylene chloride-ethyl acetate to afford 6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl (4-morpholinophenyl)carbamate (34 mg, yield 5%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.CCOC(C)=O>[CH3:8][C:2]([N:9]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)NCc1ccccc1
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CC(C)(C)N(Cc1ccccc1)C(=O)C(=O)OC
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a solution of methyl 3-methyl-3-[(phenylmethyl)amino]butanoate (5.5853 g, 25.24 mmol) in THF (125 mL) was added N,N-diisopropylethylamine (6.6 mL, 37.89 mmol). The solution was cooled to 0° C., and methyl chloro(oxo)acetate (2.55 mL, 27.73 mmol) was added dropwise. The mixture was then allowed to stir and warm to room temperature overnight. The mixture was diluted with EtOAc (200 mL) and washed with 1 N aq. HCl (100 mL), followed by sat. aq. NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was crystallized from EtOAc—hexanes to give a white solid that was collected by vacuum filtration and washed with hexanes. The resulting methyl 3-methyl-3-[[(methyloxy)(oxo)acetyl](phenylmethyl)amino]butanoate (7.0709 g, 91%) was obtained as a white solid. LCMS: (M+H)+: 308.1.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.[F:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl[C:32]1C(C(F)(F)F)=CC=CC=1C(Cl)=O>>[F:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=3)[CH:9]=[N:10][C:11]=2[CH:12]1[CH3:32])=[O:21]
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Product: CC1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1F

Procedure:
Example 19 was prepared in an analogous way as Example 11 substituting Intermediate 3 for Intermediate 1 and Intermediate 13 for Intermediate 12 in Step A. 1H NMR (500 MH, CDCl3) δ 8.53 (dd, J=12.7, 11.7 Hz, 1H), 8.03-7.99 (m, 1H), 7.92-7.80 (m, 1H), 7.70-7.60 (m, 2H), 7.40-7.27 (m, 3H), 5.78 (s, 1H), 5.10-4.56 (m, 1H), 3.75-3.31 (m, 1H), 3.31-2.76 (m, 2H), 1.83-1.38 (m, 3H). MS (ESI): mass calculated for C20H16F4N4O, 404.13. m/z found 405.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[CH:3]=1.Cl.[CH:18]1([C:21]2([F:25])[CH2:24][NH:23][CH2:22]2)[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(O)(C)C>CCCCCC>[CH:18]1([C:21]2([F:25])[CH2:24][N:23]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]4[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=4)[CH:3]=3)[CH2:22]2)[CH2:20][CH2:19]1
Reactant: FC1(C2CC2)CNC1
Reactant: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CSc1nc(Nc2cc(C)n[nH]2)cc(N2CC(F)(C3CC3)C2)n1
Temperature: 85 °C
Yield: 80 %

Procedure:
To a mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (150 g, 0.58 mol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (132.2 g, 0.87 mol) was added diisopropylethylamine (208 g, 1.61 mol) and isopropanol (1.125 L) and then heated to reflux for 23 hours. The reaction was cooled to slightly hazy solution to 85° C. and filtered and the homogeneous solution concentrated to a minimal volume. EtOAc was added (1 L) and concentrated to minimal volume. EtOAc (1 L) and H2O (1 L) were added and the layers separated (organic started to crystallize product during the extraction). The aqueous layer was further extracted with EtOAc (500 ml). Concentrated the 1st organic to dryness to give a white solid. Hexane (750 ml) was added to the 2nd organic extract and the slurry was stirred at ambient temperature, then cooled to 0° C. for 30 min. Filtered and washed with copious Heptane. The filter cake was dried under vacuum. The filter cake and the white solid from the 1st extraction were combined to afford 155.1 g of the desired product. (155.1 g, 77%). 1H NMR (DMSO, 400 MHz) 0.44 (2H, m), 0.60 (2H, m), 1.38-1.43 (1H, m), 2.18 (3H, s), 2.42 (3H, s), 3.89-3.97 (4H, m), 5.92 (1H, br s), 6.04 (1H, br s), 9.23 (1H, s), 11.86 (1H, s). ES+ 335
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=Nc1ccc(CO)cc1)NC(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The alcohol (0.282 g, 0.771 mmol) from above was dissolved in CH2Cl2 (7 mL), treated with activated MnO2 (0.696 g, 8.01 mmol) and stirred at room temperature overnight. The mixture was filtered through Celite© and the cake was washed with CH2Cl2. The solvent was removed from the filtrate under reduced pressure and provided N,N′-bis-(tert-butoxycarbonyl)-N″-(4-formyl-phenyl)-guanidine (0.260 g, 93%) as a white solid. 1H NMR (CDCl3) δ 1.53 (s, 9H), 1.55 (s, 9H), 7.85 (s, 4H), 9.93 (s, 1H), 10.34 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH:70]([O:74][CH2:75][CH3:76])[O:71][CH2:72][CH3:73]>CN(C=O)C.O>[CH2:72]([O:71][CH:70]([O:74][CH2:75][CH3:76])[CH2:69][CH2:68][NH:67][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[O:24])[CH:21]=[CH:22][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[CH3:73]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: CCOC(CCN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (200 mg, 0.45 mmol) in 10 ml of anhydrous DMF were added HATU (205 mg, 0.54 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (100 mg, 0.68 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.46 g), sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.44 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.40 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.78 g, 69%).