Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl.CCOCC>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(OC(=O)c2ccccc2)c1
Yield: 95.5 %

Procedure:
To a solution of (E)-N-methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetamide (0.21 g) in dichloromethane (5 ml), benzoyl chloride (0.12 g) and triethylamine (0.20 g) were added, and the resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ether, washed with dilute hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution. The solvent was dried and removed, and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1>ClCCl.CO.[Pd]>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1
Reactant: CCOC(=O)c1cc(OC)c2c3ncccc3c(=O)n(COC)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc(OC)c2c3c(c(=O)n(COC)c2c1)CCCN3
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The compound (776.5 mg, 2.27 mmol) prepared in step 6 was dissolved in dichloromethane and methanol, added with 10%-palladium (Pd) (80.0 mg). The resulting mixture was stirred at room temperature for 20 hours under hydrogen gas. After completion, 10%-palladium (Pd) was removed by celite-filter and the solvent was concentrated under reduced pressure. The residue was then purified by flash column chromatography (dichloromethane:ethyl acetate=3:1) to obtain the title compound (458 mg, yield: 58.2%, white solid).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:21][CH:22]=2)=[O:16])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:19][CH:18]=2)=[O:16])[CH2:8]1)(=[O:4])=[O:3]
Reactant: O=C(NCC1CCCNC1)c1cnc(-c2cccc(F)c2)nc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.523 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride (0.523 mmol) and triethylamine (2.62 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at 0° C. for an hour, and then stirred at room temperature overnight. The reaction mixture is washed with water (20 mL). The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with EtOAc to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl)-amide as a solid. MS: 393 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.43-1.95 (m, 4H), 2.10-2.23 bs, H), 3.04-3.50 (m, 5H), 3.60-3.78 (m, H), 6.71-6.90 (bs, N—H), 7.18-7.23 (m, H), 7.42-7.57 (m, H), 8.18-8.37 (q, 2H), 9.20 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>>[OH:32][CH:30]([CH3:31])[CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CC(O)CCN
Product: CC(O)CCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxy-benzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 4-amino-2-butanol in a manner similar to that described in Example 11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:17]=[C:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:10]3[C:9](=[O:18])[CH:8]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29]Br>O1CCCC1>[Br:29][CH:12]1[C:11]2=[N:17][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)=[CH:8][C:9](=[O:18])[N:10]2[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: BrBr
Reactant: O=c1cc(-c2ccncn2)nc2n1CCOCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 5.00 g (20.47 mmol) of pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in dry tetrahydrofuran (200 mL) under argon at −40° C. was added 22.52 mL (22.52 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −40° C. for 10 min and 1.10 mL (21.49 mmol) of bromine was added rapidly. The reaction was stirred at −40° C. during 20 minutes and the reaction mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (cyclohexane/ethyl acetate: 80/20 to 70/30) to afford 2.18 g (33%) of product.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 4-fluoro-2-methoxybenzonitrile (320 mg) and lithium carbonate (210 mg), the title compound was obtained as a pale-yellow solid (yield: 195.8 mg, yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH3:10])[C:4](=[O:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6](=[O:8])[N:5]([CH2:9][CH3:10])[C:4](=[O:11])[CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
A mixture of 6-chloro-3-ethylpyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (1.68 g) and potassium carbonate (0.48 g) in DMF (20 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (1.3 g, 70%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C>CC#N>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCN1CCc2ccccc2C1)Cc1ccccn1
Reaction time: 48 h
Yield: 73 %

Procedure:
The compound 2 (0.44 g, 1.13 mmol), 1,2,3,4-tetrahydroisoquinoline (0.22 g, 1.69 mmol) and triethylamine (0.218 g, 1.69 mmol) were added to 300 mL CH3CN, and the solution was stirred for two days. Purification was carried out on a silica gel TLC plate that was developed in 4% methanolic NH3 (7 M NH3 in methanol)/96% CH2Cl2. The product was obtained as pale yellow oil (73%). 1H NMR (CDCl3) δ 8.488 (dd, 1H, Ar), 7.616 (ddd, 1H, Ar), 7.573 (dd, 1H, Ar), 7.497 (dd, 1H, Ar), 7.219 (ddd, 1H, Ar), 7.090 (m, 4H, Ar), 7.004 (d, 1H, Ar), 6.933 (ddd, 1H, Ar), 6.833 (d, 1H, Ar), 3.789 (s, 3H, —OCH3), 3.766 (s, 2H, —CH2—), 3.671 (s, 2H, —CH2—), 3.608 (s, 2H, —CH2—), 2.895 (t, 2H, —CH2—), 2.712 (t, 2H, —CH2—), 2.491 (t, 2H, —CH2—), 2.455 (t, 2H, —CH2—), 1.554 (m, 4H, —CH2—CH2—), 1.298 (m, 4H, —CH2—CH2—). Mass Spec.=443.62 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (60 mg, 1.0 eq) dissolved in THF (2.5 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.20 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. Acetone (0.07 ml, 4.0 eq) was added and reaction mixture was allowed to warm up to −40° C. and stirred for 1 h. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 46. MS (Q1) 298 (M)+.
Reaction SMILES: [C:1](O)(=O)CCC(O)=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:17]=3[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH:30]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:29]3)=[N:15][C:14]=2[CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.[Cl-].[Na+]>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:17]=3[C:16]([N:28]3[CH2:33][CH2:32][N:31]([CH3:1])[CH:30]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH2:29]3)=[N:15][C:14]=2[CH:44]=1
Reactant: COc1ccc(CCC2CN(C3=Nc4cc(F)ccc4Nc4ccc(C(F)(F)F)cc43)CCN2)cc1
Reactant: O=C(O)CCC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(CCC2CN(C3=Nc4cc(F)ccc4Nc4ccc(C(F)(F)F)cc43)CCN2C)cc1
Yield: 75 %

Procedure:
Dissolve the free base obtained from Example 609 (0.078 g, 0.16 mmol) in dichloromethane (8 ml). Add sodium triacetoxyborohydride (0.066 g, 0.31 mmol) and formaldehyde (0.005 g, 0.16 mmol, 0.013 g of a 37% aqueous solution) and stir the mixture for two hours at ambient temperature. Dilute the mixture with saturated aqueous sodium chloride (50 mL) and extract three times with dichloromethane. Combine the organic layers, dryover sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% of a stock mixture of 80% dichloromethane with 20% hexanes and going to 85% of the stock mixture with 15% 2M ammonia in methanol, gives the free base of the title compound (0.062 g, 0.12 mmol, 77% yield) as a yellow amorphous solid. It is then converted to the succinate salt as described previously: Mass Spectrum (m/e): 513(M+1); Exact Mass Spec: Calc. 513.2278; Found 513.2284.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1ccc(Cl)c(B(O)O)c1
Product: Cc1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 49.7 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-methylphenylboronic acid (available from Combi-Blocks Inc.; 85 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-methyl-biphenyl-2-carboxylic acid (59 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 3H), 8.51 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.19-7.24 (m, 1H), 7.18 (s, 1H), 2.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide and (chloromethanetriyl)tribenzene (1.55 g, 5.56 mmol) in DMF (10 mL) was added triethylamine (0.56 g, 5.56 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (10:1) to give 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.1 g, 73%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 8.30 (s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.38-7.25 (m, 10H), 7.19-7.15 (m 5H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:8]2[CH2:18][C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cl)cc2n1CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a stirred solution of methyl 6-chloroindole-2-carboxylate (9.8 g, 46.7 mmol) (D. Knittel, Synthesis, 1985, 2, 186–188) in DMF (80 mL) under Ar at ambient temperature was added sodium hydride (60%; 2.80 g, 70 mmol) portionwise over 10 min. After 30 min, chloroacetonitrile (5.9 mL, 93.2 mmol) was added dropwise and the resultant mixture was heated at 75° C. (bath temp.) for 45 min; then allowed to cool. The reaction mixture was poured onto ice (500 mL) and the solid product was filtered, washed with ice-cold water (100 mL), and triturated with refluxing ethanol (150 mL). After allowing to cool to ambient temperature, then cooling in ice, the solid product was filtered-off and washed with ice-cold ethanol (50 mL) to afford the title compound (9.49 g, 82%) as a light grey solid: mp 177–8° C.; IR νmax (Nujol)/cm−1; 3094, 2955, 2925, 2854, 1713, 1613, 1568, 1527, 1519, 1448, 1421, 1398, 1378, 1336, 1306, 1260, 1150, 1108, 1060, 943, 908, 834, 802, 761, 737, 682, 618, 597, 518 and 478; NMR δH (400 MHz, DMSO-d6) 3.95 (3H, s), 5.56 (2H, s), 7.22 (1H, dd, J 8.5, 2 Hz), 7.34 (1H, d, J 1 Hz), 7.43 (1H, br s) and 7.62 (1H, d, J 8.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.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>[CH:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=1)=[O:5]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cccc(Cl)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cccc(C)c2C=O)cn1
Temperature: 100 °C

Procedure:
2-chloro-6-methylbenzaldehyde (156 mg, 1.01 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (434 mg, 1.25 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), and 2M K3PO4 (aq) (1.0 mL, 2.00 mmol) were dissolved in 1,4-dioxane (3.0 mL) and heated to 100° C. After 4 h the resulting mixture was cooled to room temperature, diluted with DCM, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:33][C:34]([CH3:37])([OH:36])[CH3:35]>C(O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(O)CCl
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(O)CN1CCN(c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)c[nH]3)cn2)CC1
Yield: 54.6 %

Procedure:
(Reference: Ind. Acad. Sci. 1939, 49, 101-4.) A solution of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (155 mg, 0.41 mmol), sodium carbonate (66 mg, 0.62 mmol, 1.5 equiv) and 1-chloro-2-methyl-propan-2-ol (51 μl, 53 mg, 0.50 mmol, 1.2 equiv) in 50% aqueous ethanol (20 ml) under nitrogen atmosphere was heated at reflux overnight. The reaction mixture was then diluted with brine and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (50% THF/0.5% ammonium hydroxide/hexanes) provided the desired product (100 mg, 54%). MS m/z 446 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1C=CC=CC=1.CO>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCS2
Reactant: C1CNCCN1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: Nc1nc2c(c(N3CCNCC3)n1)SCCC2
Yield: 80.2 %

Procedure:
11 g of 2-amino-4-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was dissolved in 150 ml of benzene and 30 g of anhydrous piperazine was added thereto while hot. After heating for 3 hours, the mixture was concentrated under reduced pressure and water was added thereto. The mixture was rendered alkaline with potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain crystals. The resulting crystals were converted into the corresponding hydrochloride in methanol and, after treatment with activated carbon, the hydrochloride was again converted into a free base form. The free base was recrystallized from a mixture of chloroform and diethyl ether to obtain 11 g of 2-amino-4-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 176°-178° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.