Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][C:49]=1[F:54].C([O-])([O-])=O.[Cs+].[Cs+].N(Cl)Cl.Cl[C:65]1[C:66]2[CH:82]=[CH:81][CH:80]=[N:79][C:67]=2[N:68]=[C:69]([C:71]2[CH:76]=[C:75]([Cl:77])[CH:74]=[CH:73][C:72]=2[F:78])[N:70]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Cl:77][C:75]1[CH:74]=[CH:73][C:72]([F:78])=[C:71]([C:69]2[N:70]=[C:65]([NH:47][C:48]3[CH:53]=[CH:52][N:51]=[CH:50][C:49]=3[F:54])[C:66]3[CH:82]=[CH:81][CH:80]=[N:79][C:67]=3[N:68]=2)[CH:76]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2cccnc2n1
Reactant: Nc1ccncc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: ClNCl
Solvent: C1COCCO1
Product: Fc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2ncccc12
Temperature: 110 °C
Yield: 21.7 %

Procedure:
To a suspension of dioxane (5 ml), Pd(OAc)2 (50 mg), BINAP (20 mg), 4-amino-3-fluoro-pyridine (42 mg) and Cs2CO3 (200 mg) was added the crude imino chloride, 4-Chloro-2-(5-Chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.34 mmol) in a sealed tube. The reaction mixture was heated to 110° C. for 15 h. The reaction mixture was cooled to r.t. and filtered through Celite® and the crude material was purified by silica gel flash column chromatography (95% to 5% gradient CH2Cl2/EtOAc) to afford [2-(5-Chloro-2 -fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(3-fluoro-pyridin-4-yl)-amine (27.3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:24])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].BrC1C=C2C(=CC=1)NC(=O)C(OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:24])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Product: N#Cc1ccc(Oc2c(O)c3cc(Br)ccc3[nH]c2=O)cc1

Procedure:
The title compound was prepared using methyl 5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate (Intermediate 10, step b) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCNCC1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: CCN1CCN(c2nccnc2OCCOc2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (72%) of the title product. HRMS m/z calcd for C18H23ClN4O2 (M)+ 362.1510, found 362.1526. Anal. (C18H23ClN4O2) C, H, N.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@@H:27]([CH:32]=O)[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@@H:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=C[C@@H]1Cc2ccc(Br)cc2C1
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@@H]2Cc3ccc(Br)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and (R)-5-bromo-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H31BrClN3O (m/e) calcd 515.1339, obsd 516.2 (M+H).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](O)[C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([NH:32][C:33](=[O:49])[C:34]4[C:39]([F:40])=[CH:38][CH:37]=[C:36]([NH:41][S:42]([CH2:45][CH2:46][CH3:47])(=[O:44])=[O:43])[C:35]=4[F:48])[CH:30]=3)[NH:25][CH:24]=2)=[CH:18][CH:17]=1>CC#N>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([NH:32][C:33](=[O:49])[C:34]4[C:39]([F:40])=[CH:38][CH:37]=[C:36]([NH:41][S:42]([CH2:45][CH2:46][CH3:47])(=[O:44])=[O:43])[C:35]=4[F:48])[CH:30]=3)[NH:25][CH:24]=2)=[CH:20][CH:21]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(O)c4ccc(Cl)cc4)c3c2)c1F
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Cc4ccc(Cl)cc4)c3c2)c1F
Temperature: 80 °C
Yield: 85.6 %

Procedure:
Triethylsilane (0.0590 mL, 0.355 mmol) and trifluoroacetic acid (“TFA”; 0.0180 mL, 0.234 mmol) were added to N-(3-((4-chlorophenyl)(hydroxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.009 mmol) in CH3CN (1 mL). The solution was warmed to 80° C. for 10 minutes. The solution was cooled and concentrated under reduced pressure to provide N-(3-(4-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (4 mg, 82.5%). 1H NMR (400 MHz, CD3OD) δ 8.63-8.44 (m, 1H), 8.30-8.32 (m, 1H), 7.62-7.68 (m, 1H), 7.35 (s, 1H), 7.27 (s, 4H), 7.10-7.15 (m, 1H), 4.11 (s, 2H), 3.09-3.13 (m, 2H), 1.84-1.89 (m, 2H), 1.03-1.07 (m, 3H); m/z (APCI-pos) M+1=519.1.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]#[N:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:25]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16](=[S:25])[NH2:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: S
Reactant: Cc1nc(CNC(=O)OC(C)(C)C)sc1C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1nc(CNC(=O)OC(C)(C)C)sc1C(N)=S
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-methylthiazole [sic] (7.5 g, 29.61 mmol) was dissolved in pyridine (30 ml), and triethylamine (27 ml) was added. The solution was saturated with hydrogen sulfide at 0° C. and then left to stand for 48 hours at room temperature. The solvent was subsequently removed on a rotary evaporator, and the residue was taken up in ethyl acetate, washed with 20% strength potassium hydrogen sulfate solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator, and the crude product was dissolved in dichloromethane and precipitated with petroleum ether. The product which had precipitated was filtered off with suction and dried in a vacuum drying oven [lacuna] 40° C. Yield: 7.1 g (24.7 mmol, 83%).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([OH:22])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([OH:22])[C:8]2=[S:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1c(O)c(CCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 85.2 %

Procedure:
Reaction of 159c (0.055 g, 0.18 mmol) and P4S10 (0.051 g, 0.115 mmol) under neat conditions as described for synthesis of 162b gave compound 162c (0.032 g, 55%) as a olive green solid. δ 8.50 (s, 1H), 7.81 (m, 3H), 7.36 (m, 4H), 6.94 (d, J=7.6 Hz, 1H), 6.62 (t, J=6.8 Hz, 1H), 4.54 (t, J=7.6 Hz, 2H), 4.46 (t, J=6.4 Hz, 2H), 2.03 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.51, 155.08, 147.73, 131.02, 130.36, 128.79, 128.13, 125.58, 119.91, 113.87, 112.10, 56.96, 49.41, 27.02, 25.08. HRMS (EI) calcd for C17H18N4OS [M]+ 326.1201. found 326.1200.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.[CH3:25]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 120 °C

Procedure:
To a mixture of 0.50 g 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 31) and 0.12 g methylboronic acid in 17 ml toluene are added 0.83 g potassium phosphate tribasic, 0.029 g palladium acetate and 0.11 g S-PHOS. The reaction mixture is heated for 1 h under microwave irradiation to 120° C. This mixture is worked up by diluting with water and extraction with dichloromethane. The organic layers are dried over Na2SO4 and concentrated to yield the crude product, which is purified by chromatography on silica gel (ethyl acetate/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:28][C:25]1[CH:24]=[CH:23][C:22]([C@H:21]2[C:14]3=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20]2)=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of (3-chlorophenyl)boronic acid (167 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 mL), and powdered 4A MS (1.50 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (34.0 mg) as a white solid.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:23][CH:24]([CH3:26])[CH3:25].[ClH:27]>CC#N.[Cu]Cl>[Cl:27][C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: Cl
Reactant: COC(=O)c1cc(OC(C)C)c(N)c(OC(C)C)c1
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)c1cc(OC(C)C)c(Cl)c(OC(C)C)c1
Temperature: 65 °C
Yield: 36 %

Procedure:
A suspension of copper (I) chloride (129 mg, 1.31 mmol) and tert-butyl nitrite (155 μL, 1.31 mmol) in anhydrous MeCN (2 mL) was stirred at 65° C. A solution of methyl 4-amino-3,5-diisopropoxybenzoate (4) (233 mg, 0.872 mmol) in anhydrous MeCN (1 mL) was added dropwise. Once the addition was complete the mixture was allowed to cool to RT and poured on to 20% HCl (5 mL). The mixture was partitioned between DCM (10 mL) and aq. ammonia (35%, 5 mL), the phases were separated and the organic solution was further washed with ammonia solution (17.5%, 10 mL), and brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-chloro-3,5-diisopropoxybenzoate (93 mg, 36% yield) as a colourless oil: m/z 287 [M+H]+ (ES+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:21][C:22]1[N:27]=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2cncc(F)c2)c1C#N
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamine.2HCl (165 mg, 0.48 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (60 mg, 0.36 mmol) and DIPEA (315 μL, 1.82 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 364 as a white solid (21 mg, 15%). LCMS (Method K): RT 3.04 min [M+H]+ 407.04. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.61 (1H, d, J=1.63 Hz), 8.02 (1H, d, J=9.22 Hz), 7.77 (1H, dd, J=8.80, 4.84 Hz), 7.55 (1H, d, J=7.75 Hz), 7.15 (1H, ddd, J=9.84, 8.79, 2.50 Hz), 7.07 (1H, dd, J=8.96, 2.48 Hz), 7.05-6.58 (2H, m), 5.53 (1H, m), 2.18 (3H, s), 1.54 (3H, d, J=6.75 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.CO>C1COCC1.O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2′-Fluoroacetophenone (25 g, 180 mmol) and (S)-(−)-2-methyl-CBS-oxazaborolidine (6.02 g, 22 mmol) were combined in THF (200 mL). Borane methyl sulfide complex (2M in THF; 59.4 mL, 119 mmol) was added over 20 minutes, and the reaction was stirred at room temperature for 30 minutes. Methanol was added, and the mixture was worked-up with dichloromethane and water. The organic layer was concentrated to give (R)-1-(2-fluoro-phenyl)-ethanol in 90.6% e.e.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:9][N:8](COCC[Si](C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1.CC1NC2N=CN=C(N3CCOCC3)C=2C=1C1C=C(C=CC=1)C#N>>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)cn1
Agent: Cc1[nH]c2ncnc(N3CCOCC3)c2c1-c1cccc(C#N)c1
Product: Cn1cc(-c2c[nH]c3ncnc(Cl)c23)cn1

Procedure:
4-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C2) was converted to the product using the method described for synthesis of 3-[6-methyl-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (2) in Example 2. In this case the product, obtained as a yellow solid, was purified by recrystallization from ethyl acetate, rather than via preparative HPLC. Yield: 1.0 g, 4.3 mmol, 43% over two steps. LCMS m/z 234.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.66 (brs, 1H), 8.58 (s, 1H), 7.91 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.63 (d, J=0.7 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[S:7]1(=[O:32])=[O:31].C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[S:7]1(=[O:32])=[O:31]
Reactant: CN1c2nc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 1 h

Procedure:
tert-Butyl 5-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3,3a,4,6a-tetrahydrocyclopenta[c]-pyrrole-2(1H)-carboxylate (24-1, 1.7 g, 3.4 mmol) was added to a mixture of DCM (28 mL) and TFA (7 mL) and stirred for 60 min. Following this duration, the contents were cautiously added to a mixture of saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange semi-solid. The material was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.C(O[CH2:18][C:19]1[S:23][C:22]([NH:24][C:25]([C:27]2[CH:28]=[C:29]([Cl:44])[C:30]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)=[O:26])=[N:21][C:20]=1[C:45]1[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=1)(=O)C>CN(C)C1C=CN=CC=1.CCO>[Cl:44][C:29]1[C:30]([N:33]2[CH2:34][CH2:35][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:38]2)=[N:31][CH:32]=[C:27]([C:25](=[O:26])[NH:24][C:22]2[S:23][C:19]([CH2:18][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[C:20]([C:45]3[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=3)[N:21]=2)[CH:28]=1
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(COC(C)=O)s3)cc2Cl)CC1
Reactant: CNCCOC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)CCOC)s3)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
39 μl of N-(2-methoxyethyl)methylamine, 51 μl of triethylamine and 23 mg of 4-(dimethylamino)pyridine were added to a 6 ml EtOH suspension of 107 mg of ethyl 1-(5-{[5-[(acetoxy)methyl]-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 50° C. for 2 hours. After the solvent was distilled off, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with EtOAc, and washed with water and with brine(saturated sodium chloride aqueous solution). The resulting product was dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a hexane:EtOAc (10:1 to 3.5:1) as an elution solvent to obtain 90 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
Reaction SMILES: C(OC1C(F)=CC=C2C=1C(CCN(C)C)=CN2)C1C=CC=CC=1.[CH2:24]([N:26]1[C:34]2[C:29](=[C:30]([OH:36])[CH:31]=[C:32]([F:35])[CH:33]=2)[C:28]([CH2:37][C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=O)=[CH:27]1)[CH3:25]>>[CH2:24]([N:26]1[C:34]2[CH:33]=[C:32]([F:35])[CH:31]=[C:30]([OH:36])[C:29]=2[C:28]([CH2:37][CH2:38][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:27]1)[CH3:25]
Reactant: CCn1cc(CC(=O)N2CCOCC2)c2c(O)cc(F)cc21
Agent: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: CCn1cc(CCN2CCOCC2)c2c(O)cc(F)cc21
Yield: 27 %

Procedure:
Following the procedure used to prepare compound 1-7a (step 6 scheme 1), compound 11-4 gave compound 11-5 (41 mg, 27%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH2:32]([NH2:34])[CH3:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:34][CH2:32][CH3:33])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CCN
Solvent: CO
Product: CCNCCOc1ccc(C(=C(CC)c2ccc3oc(Cl)cc3c2)c2ccc(O)cc2)cc1
Yield: 54 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with ethanamine (3 mL) in MeOH (8 mL) under reflux to give the desired product (38 mg, 54%, Z/E=1/1.2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 & 7.03 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H), 6.83 & 6.75 (d, J=8.8 Hz, 2H), 6.71 & 6.65 (d, J=8.6 Hz, 2H), 6.44 (s, 1H), 6.45 & 6.40 (d, J=8.4 Hz, 2H), 4.10 & 3.92 (t, J=4.8 Hz, 2H), 3.04 & 2.93 (t, J=4.8 Hz, 2H), 2.78 & 2.71 (q, J=7.2 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 1.18 & 1.13 (q, J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(O)C.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:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
To a solution of 2-bromonitrobenzene (646 mg) in THF (17 ml) under nitrogen was added tetrakis(triphenylphosphine)palladium (0) (900 mg). The resulting mixture was stirred at room temperature for 20 min, then a solution of 4-chlorophenylboronic acid (1.0 g) in ethanol (17 ml) was added and the resulting mixture stirred at room temperature for 1 hr. 2M sodium carbonate (17 ml) was then added and the reaction heated to reflux for 2 hrs. The mixture was then allowed to cool and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and the aqueous layer removed. The organic phase was washed with brine (20 ml), dried (magnesium sulfate), filtered and concentrated. The reside was purified by flash chromatography (0–10% ethyl acetate/hexane) to afford the sub-title compound as a yellow solid (646 mg): 1H NMR (400 MHz, CDCl3) δ 7.24–7.31 (2H, m), 7.41–7.47 (3H, m), 7.52 (1H, m), 7.65 (1H, m), 7.90 (1H, d).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[CH:14]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C([NH2:27])(=O)C.B(F)(F)F.CCOCC>C(OCC)(=O)C>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[N:27]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9][CH:10]=2)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: CC(N)=O
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A stirred solution of 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 35, 1.10 g, 3.12 mmol), acetamide (0.921 g, 15.59 mmol) and boron trifluoride diethyl etherate (0.565 g, 3.98 mmol) was heated at 140° C. for 2 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.401 g, 39%) as a yellow viscous oil.