Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1>C(OCC)(=O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Reaction time: 48 h

Procedure:
Sitagliptin free base (4.0 gms) and ferulic acid (1.90 gms) were dissolved in ethyl acetate (32 ml) at 60° C. to 65° C. and the resultant clear solution left for slow solvent evaporation at room temperature for 48 hours. Precipitated solids were filtered off and dried at 50° C. to 55° C. for 6 hours to obtain the title compound. Yield: 3.48 gms.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=1>CN1CCCC1=O.O>[F:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][CH2:19][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:6]1=2
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(CCBr)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 4632.5 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0022 mmol) was dissolved in N-methyl 2-pyrolidone (4.0 mL). Powdered potassium hydroxide (1 g, 0.008 mol) was added and heated at 100° C. for 2 h. 4-(2-Bromo-ethyl)-2-fluoro-1-methoxy-benzene (0.520 g, 0.0022 mol) was added at the room temperature and stir for 0.5 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.038 g, 4% yield). 8-Chloro-5-[2-(3-fluoro-4-methoxy-phenyl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0038 g, 0.00010 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00010 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.016 g, 34% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH2:36][Zn+])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:33]5[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(Cl)nc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 6-chloro-pyridin-3-ylmethylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.17 min; Mass spectrum (ESI+): m/z=475/477 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].C(N(CC)CC)C.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(O)C>[CH2:21]([NH:24][CH2:2][CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Yield: 67.6 %

Procedure:
A solution of sodium hydroxide (7.8 g, 0.195 mol) in water (20 ml) was added to a solution of 2,4,6-trichlorophenol (38.0 g, 0.192 mol) in ethanol (200 ml). 1,2-dibromoethane (47 g, 0.25 mol) was then added and the resultant mixture was refluxed overnight. On cooling, the solid was filtered off and the filtrate concentrated under reduced pressure. Ether was added to the residue and the solution was then washed with dilute sodium hydroxide solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethanol to give 1-bromo-2-(2,4,6-trichlorophenoxy)ethane as a white solid (39.4 g). A mixture of the 1-bromo-2-(2,4,6-trichlorophenoxy) ethane (20.0 g, 0.066 mol), triethylamine (6.7 g, 0.066 mol) and propylamine (3.9 g, 0.066 mol) in ethanol (500 ml) was then refluxed overnight. After removal of the solvent by evaporation, the residue was dissolved in ether, washed with water and dried (MgSO4). Evaporation of the solvent left an oil which, after flash chromatography on silica gel using chloroform as the eluant, yielded N-propyl-N-2-(2,4,6-trichlorophenoxy)ethylamine as an oil (12.6 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:36][O:37][C:38](=[O:41])[CH2:39]Cl.O>CN(C=O)C>[CH3:36][O:37][C:38](=[O:41])[CH2:39][N:26]([CH3:27])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:28])=[O:29]
Reactant: COC(=O)CCl
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(C)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.047 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.071 mmol) and chloro-acetic acid methyl ester (0.071 mmol). Stirred at 40° C. for 2 h and then added H2O (1.5 mL). Extracted with EtOAc (3×1 mL) and the combined organic phases were washed with brine (1 mL) and concentrated in vacuo. The residual oil was treated with TFA (1 mL) at rt for 1 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)C(Br)CC(O)=O)=[CH:3][CH:2]=1.ClCCl.CO.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]#[C:27][C:26]([OH:29])=[O:28])=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: O=C(O)CC(Br)C(Br)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared analogously to Example 3.4.b. from 3-biphenyl-4-yl-2,3-dibromopropanecarboxylic acid. Yield: 2.8 g (96.8% of theory); C15H10O2 (M=222.24); melting point: 170° C.; calc.: molecular ion peak (M+H)+: 223; found: molecular ion peak (M+H)+: 223; Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid (90:10:1)).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[O:23](CCN)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCCOc1ccccc1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(COC(=O)NCCOc2ccccc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To a stirred yellow solution of VII (371.8 mg, 1.089 mmol) in anhydrous THF (10 mL) was added 2-phenoxyethylamine (165 mg, 157 μL, 1.1×1.089 mmol) and then, dropwise, triethylamine (121 mg, 168 μL, 1.1×1.089 mmol). The solution was stirred for 1.5 hours at room temperature. The colorless solution was then diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to yield 260.6 mg (67%) of a 11 as a clear light yellow oil: Rf=0.39 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.26 (td, 3J=8.0 Hz, 4J=1.1 Hz, 2H), 6.98 (d, 3J=8.0 Hz, 1H), 6.96 (m, 1H), 6.94 (d, 4J=1.0 Hz, 1H), 6.92 (dd, 3J=8.7 Hz, 1H), 6.86 (d, 3J=8.1 Hz, 2H), 5.21 (bs, 1H, NH), 5.06 (s, 2H), 4.03 (t, 3J=5.0 Hz, 2H), 3.80 (s, 3H), 3.59 (q, 3J=5.2 Hz, 2H, NCH2) and 2.29 (s, 3H). Exact mass (EST) calculated for C19H22NO6 [M+H]=360.1442. found 360.1443.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:30])[C:3]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cncc(Br)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(Br)cncc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
(5-Bromo-4-chloro-pyridin-3-yl)-methanol (400 mg, 1.80 mmol) and triphenylphosphine (566 mg, 2.16 mmol) are dissolved in DCM (20 mL) and N-bromosuccinimide (384 mg, 2.16 mmol) is added. The mixture is stirred for 4 hrs at room temperature. Then the reaction mixture is purified by flash column chromatography directly (without work-up) to give 300 mg of 3-bromo-5-bromomethyl-4-chloro-pyridine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)c1cc2ccccc2s1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To 8 g (0.0407 mol) of benzothiophene-2-carboxylic acid chloride in 150 ml of toluene there are added with stirring at room temperature 7.6 g (0.0814 mol) of anilin, then, when the addition is complete, the mixture is stirred for 5 hours at 50° C., the reaction mixture is then poured into water, and precipitate which has settled out is filtered off with suction, washed twice with water and dried. 7.9 g (77% of theory) of benzothiophene-2-carboxanilide of melting point 188° C. are obtained. ##STR10##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[S:38][C:39]([C:42]([OH:44])=O)=[CH:40][N:41]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26].CCN(CC)CC.[C:52]([NH2:61])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([CH3:54])[CH3:53]>CN(C=O)C.O>[CH2:25]([NH:27][C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[S:38][C:39]([C:42]([NH:61][C:52]([CH3:54])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH3:53])=[O:44])=[CH:40][N:41]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26]
Reactant: CCNC(=O)Nc1ccc(-c2ncc(C(=O)O)s2)cn1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)NC(C)(C)c3ccccc3)s2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.078 mg, 0.225 mmol) was added to a solution of 2-(6-{[(ethylamino)carbonyl]amino}pyridin-3-yl)-1,3-thiazole-5-carboxylic acid (Example 17, 60 mg, 0.205 mmol), Et3N (84 μL, 0.41 mmol) and cumylamine (28 mg, 0.205 mmol) in 3 mL DMF. After stirring at room temperature for two hours, the mixture was diluted with water and extracted with EtOAc. The product precipitated during the workup and it was collected by filtration, washed with water and EtOAc and dried (20 mg). MS (ESP): 410 (M+H+) for C21H23N5O2S.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCCC(O)P(=O)(CCCN)OCC
Agent: Cl
Product: CCCC(O)P(=O)(O)CCCN
Yield: 85.8 %

Procedure:
A mixture of 2.0 g ethyl 3-aminopropyl(1-hydroxybutyl)-phosphinate and 20.0 ml 2M aqueous hydrochloric acid is refluxed for 2 hours and then evaporated to dryness. The residual oil is dissolved in 10 ml of water, and re-evaporated. The residue is dissolved in 20 ml of ethanol and treated with propylene oxide and to give 1.5 g of 3-aminopropyl(1-hydroxybutyl)phosphinic acid, m.p. 188°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (2.48 mL, 32.1 mmol) was added slowly to a solution of 4-benzyloxy-butan-1-ol (5.26 g, 29.2 mmol) and Et3N (6.1 mL, 43 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo to give the title compound as a colorless liquid: yield 7.5 g (99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:42])=[O:41])=[C:36]([C:47]#[N:48])[CH:35]=2)=O)=CC=1>>[C:43]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([B:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:7][O:6]3)=[CH:13][CH:12]=2)=[CH:35][C:36]=1[C:47]#[N:48])(=[O:42])=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Product: CC1(C)COB(c2ccc(CCCC(=O)Nc3ccc(S(=O)(=O)C(C)(C)C)c(C#N)c3)cc2)OC1
Yield: 93 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 10C (430 mg, 0.930 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 10D (431 mg, 93%) as a brown foam. This crude material was taken on to the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[NH2:29]>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:29][C:28]4[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=O)C(C3CC3)O4)n2)cc(OC)c1OC

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 7.21 (m, 2H), 6.87 (s, 2H), 6.77 (d, 1H), 3.58 (s, 6H), 3.56 (S, 3H), 1.20 (m, 4H); LCMS: retention time 10.25 min; purity 96.5%; MS (m/e): 468 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:10]=1)=[O:4].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.CI>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=4)=[N:20][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4]
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CNc1ccc(Oc2cncc(C(=O)OC)c2)cc1N
Solvent: CI
Solvent: CO
Product: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) in methanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, taken up in ethyl acetate and washed with water and brine, dried, evaporated under reduced pressure. Column chromatography yielded methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate. MS: MH+=452
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:32]([F:35])([F:34])[F:33])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:32]([F:33])([F:34])[F:35])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCNCc1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCCC(=O)O)ccc3c2C(F)(F)F)CC1

Procedure:
To a solution of ethyl 4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoate (150 mg, 0.30 mmol) in THF (15 mL) was added 1M HCl (3 mL) and refluxed for 1 h. Then the reaction was concentrated to give 4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoic acid as a white solid, purified by HPLC-preparation (0.05% TFA/water:MeOH=0-95%), 50 mg, white solid (yield: 34%). ESI-MS (M+H+): 466.3 HPLC: 96.13%. 1H NMR (400 MHz, CD3OD) δ: 8.20 (d, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.65 (dd, 1H), 7.57 (d, 1H), 4.50-4.46 (m, 1H), 4.34 (s, 2H), 3.16 (t, 2H), 2.46 (d, 2H), 2.21 (d, 2H), 1.98 (t, 2H), 1.90 (d, 2H), 1.49 (q, 2H), 1.25 (q, 2H), 1.14-1.08 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1.[I:38]I>C1COCC1>[I:38][CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(I)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole (2.62 g, 38.5 mmol), triphenylphosphine (10.1 g, 38.5 mmol), and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (6.0 g, 32 mmol) were combined in 20 mL of THF and cooled in an ice bath. A freshly prepared solution of iodine (9.76 g, 38.5 mmol) in 20 mL of THF was then added at the rate of maintaining the internal temperature below 12° C. After the addition was complete, the reaction was allowed to warm to RT and stirred for 16 h. The reaction mixture was partitioned between MeOtBu and 10% NaHSO3. The aqueous layer was back extracted with MeOtBu (2×) and the combined orgnia layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 3-iodopyrrolidine-1-carboxylate as a colorless oil. MS (ESI, pos. ion) m/z: 241.6 (M−56).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[H-].[Na+].I[CH3:14]>CN(C=O)C.Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:14])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(O)cc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 3,5-dihydroxybenzaldehyde (1.0 g, 7.24 mmol) in DMF (20 mL) is treated with sodium hydride (319 mg, 8.0 mmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, the reaction is treated with iodomethane (0.50 mL, 8.0 mmol) via syringe and stirred 16 h. It is then diluted with 1 M HCl (100 mL) and extracted into EtOAc (50 mL). The EtOAc phase is washed with 1 M HCl (50 mL), water (2×50 mL) and brine (50 mL), dried over Na2SO4 then the EtOAc removed in vacuo. The title compound is obtained after chromatography (gradient elution—0-50% EtOAc in heptane).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11](/[CH:12]=[C:13]3\[O:14][C:15]4[C:22]([CH2:23][N:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[C:21]([OH:37])[CH:20]=[CH:19][C:16]=4[C:17]\3=[O:18])[C:6]2=[CH:5][CH:4]=1)#[CH:2].[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:38].[ClH:38].[C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11](/[CH:12]=[C:13]3\[O:14][C:15]4[C:22]([CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[C:21]([OH:37])[CH:20]=[CH:19][C:16]=4[C:17]\3=[O:18])[C:6]2=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.030 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.012 g, 78%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1-c1ccccc1
Temperature: 200 °C
Yield: 91.1 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (13.06 g, 92.6 mmol), 2-aminobiphenyl (31.3 g, 185.2 mmol), and potassium fluoride (8.1 g, 138.9 mmol) was prepared in a 100 mL round bottom flask. The flask was evacuated and replaced with nitrogen. The mixture was heated to 200° C. overnight. The reaction mixture was cooled and ethyl acetate and water were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was preabsorbed onto Celite and purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes. 24.5 g (91%) of product was obtained.