Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:37])=O>O>[Cl:37][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 92) 500 mg, diethylaniline 2 ml and phosphoryl chloride 4 ml is stirred at 80° C. for 30 minutes and then at 100° C. for 5 hours. After cooling, the reaction solution is poured into water in ice and the mixture is stirred at room temperature for 30 minutes. The product is extracted with ethyl acetate and the organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 7 g, solvent; chloroform) to give 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly yellow crystalline powder, 375 mg. mp 114–115° C. MS(m/z): 356(M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[C:6]2[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1sc2c(Cl)c(Cl)c(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(C)c(C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of 22.4 g of 6,7-dichloro-5-hydroxy-2,3-dimethylbenzo[b]thiophene is added a mixture of 18.23 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 15 g of potassium carbonate and 7.5 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 21/2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are separated, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. The solid is recrystallized from acetone-hexane to give 25.8 g of ethyl[ (6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetate, mp 102°-104°.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O=[Si]=O.[F:15][C:16]1[CH:17]=[C:18]([CH:23]([OH:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([C:23](=[O:26])[CH2:24][CH3:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCC(O)c1ccc(F)c(F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
In a round bottom flask containing pyridinium chlorochromate (12.5 g, 58.1 mmol) was added celite 545 (25 g) and with the help of a magnetic stirrer the solids were mixed together. 200 mL of CH2Cl2 was added followed by a solution of 1-(3,4-difluorophenyl)propan-1-ol (5.0 g, 29.1 mmol) in 10 mL of CH2Cl2 and the resulting brown suspension was stirred overnight at room temperature. The suspension was filtered through a sintered glass funnel and the solvent was removed in vacuo from the pale green colored filtrate. The green oil was then diluted with diethyl ether (200 mL) and it was filtered through a pad of celite to remove the metal impurities. The solvent was removed in vacuo to obtain 1-(3,4-difluorophenyl)propan-1-one as a pale yellow oil (3.4 g, 69% yield). It was used ion the next step without purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[SH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (0.16 g, 0.95 mmol) was dissolved in N,N-dimethylformamide (8.1 mL), and 4-mercaptophenol (0.11 g, 0.86 mmol) and triethylamine (0.27 mL, 1.9 mmol) were added thereto, followed by stirring at 25° C. for 1 hour. After the conventional treatment, the product was purified by silica gel column chromatography (eluted by n-hexane/acetone=4/1-1/1) to give 5-nitro-2-[(4-hydroxyphenyl)thio]benzaldehyde (0.18 g, 70%).
Reaction SMILES: [F:1][CH:2]([F:11])[CH:3](C(F)F)[C:4]([F:7])([F:6])[F:5].ClC(Cl)(Cl)C(=[O:18])C(Cl)Cl>>[F:5][C:4]([F:7])([F:6])[C:3](=[O:18])[CH:2]([F:11])[F:1]
Reactant: O=C(C(Cl)Cl)C(Cl)(Cl)Cl
Reactant: FC(F)C(C(F)F)C(F)(F)F
Product: O=C(C(F)F)C(F)(F)F

Procedure:
The 2-difluoromethyl-1,1,1,3,3-pentafluoropropane may be prepared by fluorinating commercially available 1,1,1,3,3-pentachloro-2-propanone to form 1,1,1,3,3-pentafluoro-2-propanone which may then be reacted with CF2 carbene to form 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene. The 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene may then be hydrogenated to form 2-difluoromethyl-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:27]([N:26]([CH3:30])[CH3:25])=[O:28])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)S[C@H]1C[C@@H](COC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 20 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (78 mg) was dissolved in 1 ml of dry pyridine, and 135 mg of 4-N,N-dimethylaminopyridine and 119 mg of dimethylaminocarbonyl chloride were added successively thereto, followed by stirring at 90° to 100° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)C>[OH:1][CH:2]([CH2:23][NH:27][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 73 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.35 g.), isopropylamine (16 ml) and ethanol (16 ml) was boiled under reflux for 2 days. Removal of the solvent in vacuo gave 7-(2-hydroxy-3-isopropylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.7 g., 73%) isolated as the hydrochloride salt, m.p. 171°-174° from ether-ethanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]#[N:10]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using α-bromo-m-tolunitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile was obtained (66%) as a colorless solid: mp 173-178° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.60-7.63 (m, 3H), 7.44-7.47 (m, 1H), 7.21-7.24 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.93-4.97 (m, 3H), 4.66-4.69 (m, 1H), 4.13-4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 131.7, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4; MS (ES+) m/z 410.8 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:38])C.CC1(C)N([O])C(C)(C)CCC1.Cl>O.CC#N.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([OH:38])=[O:28])=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCCO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a suspension of Example 27 (25 mg) in H2O/CH3CN (0.2 mL, 1:1) was added at 0° C. diacetoxyiodobenzene (35 mg) and 2,2,6,6-tetramethylpiperidine-1-oxyl (3 mg), and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with H2O, acidified with aq. HCl (1M, 0.5 mL) and extracted with EtOAc (3×5 mL) The combined organic layers were dried over Na2SO4 and concentrated to dryness. Purification by CC (CH2Cl2/MeOH 97:3) gave 8 mg of the desired product.
Reaction SMILES: OCC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NC1C=CC([CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=CC=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:10][C:9]1[CH:4]=[CH:5][C:6]([CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:7][CH:8]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC(=O)OC(C)(C)C)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 27 in place of 8-aminooctanol. 1H NMR (400 MHz, DMSO-d6) δ510.80 (s, 1H), 10.46 (s, 1H), 9.09 (s, 1H), 8.25-8.39 (m, 3H), 8.21 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.72-7.80 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.11 (t, J=8.0 Hz, 1H), 6.88 (t, J=5.4 Hz, 1H), 6.60-6.68 (m, 2H), 6.52 (d, J=8.3 Hz, 1H), 3.60 (s, 3H), 3.08-3.18 (m, 2H), 2.65-2.73 (m, 5H), 1.40 (s, 9H); ES/MS calcd. for C38H40N6O7S+ 710.3. Found m/z=710.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[I-].ClC1C=CC=C[N+]=1C.[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:19][C:16]1([F:20])[CH2:17][CH2:18][N:13]([S:10]([C:4]2[S:3][C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[F:30])=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1
Reactant: NC(=O)c1cc(S(=O)(=O)N2CCC(F)(F)CC2)sc1N
Reactant: O=C(O)c1ccccc1F
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Product: NC(=O)c1cc(S(=O)(=O)N2CCC(F)(F)CC2)sc1NC(=O)c1ccccc1F

Procedure:
A solution of 2-Amino-5-(4,4-difluoro-piperidine-1-sulfonyl)-thiophene-3-carboxylic acid amide (53 mg, 0.18 mmol), TEA (125 μL, 0.90 mmol), DMAP (7 mg, 0.054 mmol), 2-Chloro-1-methylpyridinium iodide (60 mg, 0.23 mmol) and 2-fluorobenzoic acid (33 mg, 0.23 mmol) in DCM is stirred at 80° C. overnight. The mixture is then diluted with DCM and washed with aqueous NaHCO3. The organic phase is isolated evaporated, and the residue is purified by preparative chromatography to yield the desired product.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(O)C.C[O-].[Na+].[C:17]1([N:23]=[N:24][CH:25]([C:28]#[N:29])[C:26]#[N:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([N:23]=[N:24][C:25]2[C:26]([NH2:27])=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][C:28]=2[NH2:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=C(N)c1ccncc1
Reactant: N#CC(C#N)N=Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccncc2)nc(N)c1N=Nc1ccccc1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
The intermediate 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine was prepared as follows: a mixture containing 477 g of isonicotinamidine hydrochloride, 3 liters of ethanol and 170 g of sodium methoxide was stirred for 30 minutes and to the mixture was added 340 g of α-(phenylazo)malononitrile and the reaction mixture was stirred under reflux for 5 hours and then poured into 3 liters of water. The solid that separated was collected, washed with water and dried in a vacuum oven at 90°-95° C. to yield 356 g of 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine, m.p. 302°-305° C.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)=[CH:13][CH:12]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:18]=1
Reactant: OCc1cncc(-c2ccc(Cl)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cncc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
543 mg (0.333 ml, 4.56 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 500 mg (2.28 mmol) [5-(4-Chloro-phenyl)-pyridin-3-yl]-methanol in 30 ml dichloromethane and stirred for 2 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (444 mg, 75%) used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>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:20][C:4]1[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
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: [K+]
Product: C=Cc1cnc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 65 %

Procedure:
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].Cl[C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Reactant: COc1ccc(CN)cc1OC
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(NCc5ccc(OC)c(OC)c5)nccc34)ccc2n1

Procedure:
Dissolved 3,4-dimethoxybenzylamine (3.04 ml, 20.2 mmol) in NMP (15.0 mL) and added 6-(1-chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (2.25 g, 6.72 mmol) as a solid in a sealed vessel and heated the reaction to 220° C. in the microwave 20 minutes. Dripped the reaction mixture into water and isolated the resulting precipitate. Air-dried the solid and redissolved in 2M NH3/MeOH. Concentrated in vacuo, redissolved wet slurry in EtOAc and dried the slurry over Na2SO4. Concentrated and loaded the crude material on a column, and purified the crude eluting with 20-100% EtOAc/hexanes. The pure fractions were combined and concentrated to afford 6-(1-(3,4-dimethoxybenzylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine. MS (M+H)+ 466.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:33]([O:35]CC)=[O:34])[C:6]([O:38]CC)=[N:5]2.Br.C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:33]([OH:35])=[O:34])[C:6](=[O:38])[NH:5]2
Reactant: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4nc(C(=O)OCC)c(OCC)nc4cc3Cl)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4nc(C(=O)O)c(=O)[nH]c4cc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of ethyl 6-chloro-3-ethoxy-7-(4-(((4-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)quinoxaline-2-carboxylate (64.0 mg, 113 μmol) in acetic acid (3 ml) was added 47% hydrobromic acid (0.3 ml), and the mixture was stirred for 3 hours at room temperature. After allowed to stand overnight, the mixture was stirred for 1 hour at 40° C. After cooling, ethanol was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The precipitated crystals were collected by filtration and air-dried, thereby obtaining 18.8 mg of title compound as brown powder. The residue obtained by concentrating the filtrate under reduced pressure was washed with water and air-dried, thereby obtaining additional 37.4 mg. Total yield 56.2 mg. Yield 97%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:16]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[OH:25])=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:16]([C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][C@H:20]1[OH:25])=[N+:17]=[N-:18]
Reactant: O=[N+]([O-])c1cc(F)cc(-n2cnnc2)c1
Reactant: [N-]=[N+]=NC1CCNCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@H]1CCN(c2cc(-n3cnnc3)cc([N+](=O)[O-])c2)C[C@H]1O
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A mixture of 4-(3-fluoro-5-nitrophenyl)-4H-1,2,4-triazole (200 mg, 0.96 mmol), 4-azidopiperidin-3-ol (164 mg, 1.15 mmol) and K2CO3 (199 mg, 1.44 mmol) in DMSO was heated at 100° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc (two times). The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography, (SiO2, 24 g column, 0-12% MeOH/DCM) to give Intermediate 33A (135 mg, 43%) as a yellow solid. HPLC: Rt=1.722 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=331 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([C:37]4[N:33]([CH:28]5[CH2:29][CH2:30][CH2:31][CH2:32][O:27]5)[N:34]=[CH:35][CH:36]=4)[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccnn2C2CCCCO2)n1
Temperature: 120 °C
Yield: 3.7 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (300 mg, 0.666 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (222 mg, 0.799 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.020 mmol), THF and 2M Na2CO3 solution were added in a microwave flask and heated in microwave at 120° C. for 2 h. 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (37 mg) and tetrakis(triphenylphosphine)palladium (8 mg) were added and the reaction mixture was heated in 120° C. for 1 h. The reaction mixture was diluted with DCM and washed twice with Na2CO3 solution. Organic phase was dried and evaporated to dryness. The product was purified by Flash-chromatography. Yield 3.7%. m/z [522.0+1].