Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[Cl:64]C1C=CC(B(O)O)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([Cl:64])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: Clc1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 4-chlorophenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine. NMR (DMSO-d6): δ 8.99 (bs, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.50-7.42 (m, 4H), 7.23 (bs, 1H), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=2.4 Hz), 7.00-6.94 (m, 1H), 6.73 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=8.7 Hz); LCMS: ret. time: 16.12 min.; purity: 86%; MS (m/e): 490 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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.CCO>[Cl:11][C:4]1[CH:3]=[C:2]([C:20]2[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Reactant: Clc1cc(Cl)c2c(n1)CCC2
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C=C(c2cc(Cl)c3c(n2)CCC3)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
A 250-mL round bottomed flask was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (1.05 g, 5.58 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (1.27 g, 6.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.322 g, 0.28 mmol), and Cs2CO3 (5.45 g, 16.7 mmol). Toluene (30 ml), EtOH (7.5 ml) and water (15 ml) were added. The resulting mixture was stirred under argon at 90° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 mL), hexanes (50 mL) and water (25 mL). The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.305 g, 23%) as a yellow solid. MW=233.69. 1H NMR (CDCl3, 500 MHz) δ 7.41 (s, 1H), 6.79 (t, J=2.0 Hz, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.10-3.06 (m, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.62-2.58 (m, 2H), 2.20 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(NCCc1ccccc1)c1ccc(F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=NCCc3ccccc32)cc1F
Temperature: 25 °C

Procedure:
To a 250-mL round-bottomed flask, 3,4-difluoro-N-phenethylbenzamide (1.97 g, 7.54 mmol) and phosphorus pentoxide (3.25 g, 22.9 mmol) were suspended into 40 mL of toluene. Phosphorus oxychloride (3.51 mL, 37.7 mmol) was added and the mixture was refluxed for overnight. The mixture was cooled to RT. The supernatant contained only the starting material and was removed. Ice water (75 mL) was added to the residue in the flask and stirred to break up the solid into powder. EtOAc was added and the pH was adjusted to ˜12 with 3N aqueous potassium hydroxide. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow viscous oil. The crude product was purified by silica gel chromatography (20-70% EtOAc in hexanes) to afford the title compound as a clear oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.17-7.52 (m, 7H) 3.78-3.92 (m, 2H) 2.73-2.89 (m, 2H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCNCC1

Procedure:
Step 1): 10% Pd/C was added to a solution of the N-(1-benzylpiperidin-4yl)-2-(N'-n-heptylureido)benzamide (1.4 g, 3.1 mmol) obtained in Example 41 in methanol (25 ml) under nitrogen. The mixture was shaken under 50 psi hydrogen pressure for 5 hours, and then filtered under nitrogen. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (50% methanol and 0.8% NH4OH in dichloromethane) to give N-(piperidin-4-yl)-2-(N'-n-heptylureido)benzamide: 48.4%: mp 159° C.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4])[NH2:2].[OH-].[K+].[C:31](=S)=[S:32]>CCO>[S:32]=[C:31]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][N:8]3[C:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)=[CH:12][N:13]=[C:7]3[CH:6]=2)=[N:1][NH:2]1
Reactant: S=C=S
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4n[nH]c(=S)o4)ccn23)c1
Temperature: 65 °C
Yield: 52.9 %

Procedure:
To a solution of 1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (120 mg, 0.30 mmol) and KOH (20 mg, 0.36 mmol) in EtOH (4 ml) was added carbon disulfide (241, 0.36 mmol). The reaction mixture was heated at 65° C. for 3 h, cooled and then placed in an ice bath upon which a precipitate was formed. The solid was filtered off, wash with EtOAc and Et2O, then dried to afford the title compound (69 mg). MS: [M+H]+=435.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([F:11])[CH:4]=1)#[N:2].[CH2:12](O)[CH2:13][CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:8]1[CH2:12][CH2:13][CH2:14][O:15][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCCO2)c(F)c1
Reaction time: 6 h

Procedure:
4-Cyano-2-fluorobenzaldehyde (65 g, 436 mmol) and 1,3-propanediol (36.5 g, 479 mmol; 1.1 eq.) were, together with 4-toluenesulfonic acid monohydrate (1.66 g, 8.72 mmol; 0.02 eq.), initially charged in toluene (1000 ml) and stirred at boiling point on a water separator for 6 h. The reaction mixture was then washed with saturated sodium bicarbonate solution (3×300 ml) and saturated sodium chloride solution (3×300 ml). The organic phase was dried over sodium sulfate and concentrated. The title compound was obtained as a solid (92 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ncc(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 16, (98 mg, 0.69 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg, 0.57 mmol) in DMF (10 mL) and CH2Cl2 (4 mL) is added HATU (272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is stirred at room temperature for 2 hrs. The crude is quenched with water and diluted in EtOAc. The organic layer is washed with water 3×, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate (122 mg). HPLC retention time=1.89 minutes (condition A); MS (m+1)=443.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3H), 2.52-2.66 (m, 2H), 2.94 (dd, 1H), 3.08 (dd, J=13.6, 6.3 Hz, 1H), 4.12 (s, 3H), 4.14-4.23 (m, 2H), 4.60-4.71 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 7.25-7.32 (m, 3H), 7.35 (t, J=7.7 Hz, 1H), 7.42 (s, 1H), 7.43-7.47 (m, 1H), 7.48-7.54 (m, 2H), 7.55 (t, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[N:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:19]2[N:24]3[N:25]=[CH:26][N:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(OC[C@H]3CCCN3)cccc2c1
Reactant: Clc1ccnc2ncnn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc2c(OC[C@H]3CCCN3c3ccnc4ncnn34)cccc2c1

Procedure:
400 mg of (R)-2-(naphthalen-1-yloxymethyl)pyrrolidine, 500 mg of the 7-chloro-[1,2,4]triazolo[1,5-a]pyrimidine prepared above and 650 mg of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 40 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 640 mg of “A1”; m.p. 74-75°;
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:26]#[N:27])=[CH:3][CH:4]=3
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(C#N)cc1-2
Temperature: 80 °C
Yield: 6 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (300 mg) (prepared as in Example 4), zinc cyanide (187 mg), and DMF (5 ml) was degassed with a stream of N2 for 0.5 h. Tetrakis(triphenylphosphine) palladium(0) (20 mg) was added and the reaction heated to 80° C. for 2 days. The reaction mixture was cooled, poured into 10% ammonium hydroxide solution and extracted into EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica, eluting with 50% EtOAc/hexane, and recrystallised from EtOAc/hexane to give the title compound (15 mg, 6%). 1H NMR (360 MHz, CDCl3) δ 8.28 (1H, s), 7.69 (1H, dd, J=8.0, 1.4 Hz), 7.54–7.50 (2H, m), 7.48–7.39 (4H, m), 4.05 (2H, s), 2.73 (3H, s), m/z (ES+) 340 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23].Cl>N1C=CC=CC=1>[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)=[O:23]
Reactant: O=C(Cl)c1cnc2ccccc2c1O
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1ccc(NC(=O)c2cnc3ccccc3c2O)cc1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
1.86 g of phenetidine were added to a suspension of 3 g of 4-hydroxy-3-quinoline-carboxylic acid chloride (described in French Pat. No. 2,340,735) in 40 ml of anhydrous pyridine and the mixture was stirred for 16 hours. 50 ml of aqueous 2 N hydrochloric acid solution were added to the mixture which was stirred for one hour and then was filtered. The recovered product was washed with water, dried at 180° C. under reduced pressure and was crystallized from 30 ml of acetic acid and then 10 ml of dimethylformamide to obtain 2.1 g of 4-hydroxy-N-(4-ethoxyphenyl)-3-quinoline-carboxamide in the form of crystals melting at 288° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][NH:29][C:28]2[N:32]=[CH:33][CH:34]=[CH:35][C:27]1=2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:29]3[CH2:30][CH2:31][O:26][C:27]4[CH:35]=[CH:34][CH:33]=[N:32][C:28]3=4)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:24])([F:23])[F:25]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1cnc2c(c1)OCCN2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2cccnc21

Procedure:
3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide; Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 2.871 min; MS m/z 533.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=O.[F:13][C:14]1[CH:15]=[C:16]([CH2:21][NH2:22])[CH:17]=[CH:18][C:19]=1[F:20]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]([F:20])=[C:14]([F:13])[CH:15]=1)=[O:7]
Reactant: NCc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccc(F)c(N)c1
Solvent: C1CCOC1
Product: Nc1cc(C(=O)NCc2ccc(F)c(F)c2)ccc1F
Temperature: 25 °C

Procedure:
A mixture comprising methyl 3-amino-4-fluorobenzoate (2 g, 11.82 mmol), (3,4-difluorophenyl)methanamine (2.54 g, 17.74 mmol) and TBD (1.646 g, 11.82 mmol) in THF (39.4 ml) was heated at 80° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM to afford the title compound.
Reaction SMILES: C(OC([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][CH:13]([O:16][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]1)=O)(C)(C)C.CO.C([BH3-])#N.[Na+].[ClH:30]>O1CCCC1.C([BH3-])#N.[Na+]>[ClH:30].[NH:9]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[NH2:8]
Reactant: CC(C)(C)OC(=O)NN=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NNC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
N′-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (4.103 g, 11.98 mmol) was dissolved in dry tetrahydrofuran (11.5 mL) and dry methanol (15.0 mL). Sodium cyanoborohydride (0.945 g, 14.29 mmol) was added portionwise. When the effervescence subsided the mixture was refluxed for 1.5 hours. At this time a small additional amount of sodium cyanoborohydride (0.047 g, 0.75 mmol) was added and refluxing was continued for another 30 minutes to insure complete reaction. After cooling to room temperature, 6N HCl (10 mL) was added, resulting in precipitation of a white solid. The mixture was heated at 70° C. for 6 hours and then cooled to room temperature and stirred for 12 hours. The reaction mixture was concentrated and azeotroped with toluene to remove nearly all of the water. The residue was then dissolved in hot isopropanol and cooled back down to room temperature. Any insoluble material was removed by filtration. The filtrate was diluted with ether and chilled. The material dropped out of solution as an oil/gum. The mother liquor was removed by decantation. The oil/gum was then washed with ether and dried in vacuo to give 4-hydrazino-cyclohexanol hydrochloride (1.920 g, 96%). A second crop (0.261 g, 13%) was collected from the mother liquor. The yield was greater than theoretical due to the presence of trapped solvent and small impurities. The material was used without any further purification.
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[O:37][CH:36]=[CH:35][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH3:34])=[N:23][N:24]4C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)[N:16]=2)[CH2:7]1)(=O)C.Cl.NCC1CCN(C(OC(C)(C)C)=O)C1.C(Cl)(=O)C.ClC1N=C(Cl)C2OC=CC=2N=1.Cl>CO>[NH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[O:37][CH:36]=[CH:35][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH3:34])=[N:23][NH:24]4)=[CH:20][CH:19]=3)[N:16]=2)[CH2:7]1
Reactant: CC(=O)NCC1CCN(c2nc(Nc3ccc4c(C)nn(C(=O)OC(C)(C)C)c4c3)nc3ccoc23)C1
Agent: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: Cl
Agent: Clc1nc(Cl)c2occc2n1
Solvent: CC(=O)Cl
Solvent: CO
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(CN)C4)c4occc4n3)ccc12
Temperature: 90 °C
Reaction time: 32 h
Yield: 61 %

Procedure:
To a solution of tert-butyl 6-(4-(3-(acetamidomethyl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (0.57 g, 1.1 mmol, prepared using E.1 from tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate hydrochloride [Astatech] with acetyl chloride, C, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with Example #3, Step B) in MeOH (12 mL) was added concentrated HCl (12 mL). The mixture was stirred for about 32 h at about 90° C. The mixture was cooled to rt, and a white precipitate formed that was collected by vacuum filtration and washed with water. The solid was dissolved in hot aqueous 1 M HCl and the suspension was filtered while hot. To the filtrate was added aqueous NH4OH to reach a pH˜9, and the resulting precipitate was collected to give 4-(3-(aminomethyl)pyrrolidin-1-yl)-N-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.27 g, 61%): LC/MS (Table 2, Method h) Rt=1.61 min; MS m/z: 364 (M+H)+. Syk IC50=A
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(CO)(CO)CC(C)C
Reactant: CI
Product: COCC(CO)(CC(C)C)CC(C)C

Procedure:
2,2-Di-iso-butyl-3-methoxy-1-propanol was prepared from 2,2-di-iso-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][C:10]1[CH:12]=[CH:13][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: BrCCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [Na]
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated. The mixture was stirred at ambient temperature for 1 hr and then added over a 3 hr period to a solution at reflux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated and the organic layer was washed with four 300 ml portions of a 5% sodium hydroxide solution once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 138 g of gummy solid as residue. This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethyl acetate in benzene to yield 69.9 g (46%) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1>CC(O)C>[Cl:19][C:20]1[N:29]=[C:28]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3.9 g of 3-chloro-4-methoxybenzylamine, 3.97 g of triethylamine and 200 ml of 2-propanol were added to 4 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes, cooled to room temperature and filtered to recover a crystalline precipitate. The precipitate was washed with water and chloroform successively to give 5.563 g of the title compound.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl:10][CH2:11][C:12](Cl)=[O:13].[CH3:15][N:16]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[CH:20]=[CH:19][C:17]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:15][N:16]1[C:26]2[C:21](=[C:22]([C:12](=[O:13])[CH2:11][Cl:10])[CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[CH:20]=[CH:19][C:17]1=[O:18]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2ccc(=O)n(C)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCl)c2ccc(=O)n(C)c12
Temperature: 0 °C

Procedure:
30 ml of nitrobenzene and 70 ml of chloroacetyl chloride (V) were added to 40 g of 1-methyl-8-methoxycarbostyril (VI), and 130 g of aluminum chloride was added slowly to the mixture while cooling with ice-water followed by allowing the mixture to react at a temperature of 60° C. for 4 hours while stirring. The reaction mixture was then poured into one liter of ice-water to precipitate the product. The precipitate was filtered, washed with diethyl ether and recrystallized from a mixture of chloroform and ethanol (2:5 by volume) to obtain 32 g of white amorphous 1-methyl-5-chloroacetyl-8-methoxycarbostyril (IV) having a melting point of 204° to 205.5° C. The product thus obtained was confirmed by elemental analysis and IR and NMR spectral analyses.