Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][S:7][CH2:8][C:4]=2[C:3]([NH2:9])=[N:2]1.[C:10]1([CH3:24])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21]>N1C=CC=CC=1>[NH2:23][C:22]1[N:2]2[N:1]=[C:5]3[CH2:6][S:7][CH2:8][C:4]3=[C:3]2[N:9]=[C:18]([C:11]2[C:10]([CH3:24])=[CH:15][C:14]([CH3:16])=[CH:13][C:12]=2[CH3:17])[C:19]=1[C:20]#[N:21]
Reactant: Nc1n[nH]c2c1CSC2
Reactant: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2C#N)CSC4)c(C)c1

Procedure:
A solution of 284 mg (2.01 mmol) of 4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-amine (Intermediate 21) and 395 mg (2.01 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 5 mL of anhydrous pyridine was stirred at reflux under air overnight (protected from moisture with a calcium sulfate drying tube) and then cooled and concentrated in vacuo. The residue was stirred with 20 mL of methanol and filtered to remove some insoluble material, which was washed with an additional 5 mL of methanol. The combined filtrate and washings were concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 5-15% ethyl acetate in hexane) afforded the title compound as a solid. LC-MS 336 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CC1C=CC(CN)=CC=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=1)=[O:35])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccnc(NC(=O)c3ccccc3)c2)cc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with p-tolylmethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(4-methylbenzyl)-isonicotinamide was obtained as a colorless solid in 35% yield: mp 135-138° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.33-9.30 (m, 1H), 8.60-8.51 (m, 2H), 8.06-8.03 (m, 2H), 7.63-7.50 (m, 4H), 6.25-7.03 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 2.28 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.0, 164.7, 152.8, 148.4, 143.6, 136.1, 135.9, 133.8, 131.9, 128.8, 128.3, 127.9, 127.3, 117.2, 112.7, 42.4, 20.6; MS (ES+) m/z 346.5 (M+1).
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: [Li]C(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise, and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil. Yield: 0.53 g (47%). (50% de 3S,4R: 50% de 3R,4R) 1H-NMR (d6-DMSO, 250 MHz): δ 0.44 (t, 3H, J=7.03 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.77 (2×d, 6H, J=6.48 Hz, —NHCH (CH2CH3)CH(CH(CH3)2)OH), 0.79-1.13 (m, 2H, —NHCH(CH2CH3)CH (CH(CH3)2)OH), 1.72 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.11 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.77 (m, 1H, —NH CH(CH2CH3)CH (CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.55 (d, 1H, J=5.21 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.15-7.46 (m, 15H, 3×Ph).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1.[Cu][C:18]#[N:19].O.[OH-].[Na+]>CN(C)C=O>[C:18]([C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1)#[N:19]
Reactant: N#C[Cu]
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC1=NS(=O)(=O)c2sc(C#N)cc2N1
Temperature: 150 °C
Yield: 2 %

Procedure:
To a solution of 6-bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (243 mg, 0.75 mmol) in dry N,N-dimethylformamide (2 ml) was added copper(I) cyanide (135 mg, 1.5 mmol) and the mixture was heated at 150° C. for 2 h under nitrogen. The dark mixture was allowed to cool to room temperature and water was added. The suspension was made basic by the addition of 1 N sodium hydroxide, filtered and the filtrate was acidified by the addition of 4 M hydrochloric acid. The resulting precipitate was purified by preparative hplc on a Source RPC 15 column using acetonitrile/water (20:80) with 0.1% TFA as eluent to afford 4 mg (2%) of the pure title compound; LC-MS: m/e 271 ((M+1)+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[C:8]4[C:23]([CH3:25])([CH3:24])[C:22]5[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=5)[C:9]4=[CH:10][C:11]=3[C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:27]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:20]1[CH:19]=[CH:18][C:17]2[C:9]3[CH:10]=[C:11]4[C:12]([CH3:16])([CH3:15])[C:13]5[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=5)[C:6]4=[CH:7][C:8]=3[C:23]([CH3:24])([CH3:25])[C:22]=2[CH:21]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)-c1ccc(Br)cc1C3(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)-c1ccc(-c2ccccc2-c2ccccc2)cc1C3(C)C
Temperature: 100 °C
Yield: 56.8 %

Procedure:
A mixture of 14.7 g (31.5 mmol) of 2,8-dibromo-6,6,12,12-tetramethyl-6,12-dihydroindeno[1,2-b]fluorene, 6.5 g (33 mmol) of biphenyl-2-ylboronic acid, 0.36 g (0.3 mmol) of tetrakis(triphenylphosphine) palladium, 32 ml of 2M Na2CO3, 60 ml of EtOH and 150 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 9.7 g (17.9 mmol, 57%). 1H NMR (CDCl3, 400 MHz): chemical shift (ppm): 7.78 (d, J=8.0 Hz, 1H), 7.65˜7.61 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.51˜7.21 (m, 10H), 7.18 (s, 2H), 7.08˜6.99 (m, 2H), 1.83 (s, 6H), 1.81 (s, 6H)
Reaction SMILES: [F:1][C:2]([F:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3]O.FC(F)(F)C(O)=O.[NH:21]1[CH2:25][CH2:24][C@@H:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:22]1>>[F:1][C:2]([F:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][N:21]1[CH2:25][CH2:24][C@@H:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:22]1
Reactant: OCC(F)(F)CCc1ccccc1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(CC(F)(F)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=364.2 (M+H+) was prepared from 2,2-difluoro-4-phenyl-butan-1-ol and (3R)-4-(pyrrolidin-3-ylsulfanyl)-phenol trifluoroacetic acid.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:37])[CH:28]=2)[N:23]=1)=[O:21]>O.O1CCCC1>[OH:21][CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:37])[CH:28]=2)[N:23]=1)[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCCCCC
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccc(F)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC#CC(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
1.32 ml of a hexane solution of 2.16 mmols of n-butyl lithium was added to a solution of 238 mg (2.16 mmols) of 1-octyne and 5 ml of tetrahydrofuran in an atmosphere of nitrogen at 0° C. and stirred at the same temperature for 15 minutes. The reaction solution was cooled to -78° C. to which a solution of 10 ml of tetrahydrofuran of 445 mg (1.80 mmols) of 2-formyl-3-methyl-4-acetoxy-6-fluoroquinoline was added, followed by heating gradually to room temperature and stirring at room temperature for 1 hour. The reaction solution was poured into 50 ml of water, extracted with ethyl acetate and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako gel C-200) (solvent: n-hexane ethyl acetate=5:1) to obtain 349 mg (yield 54 %) of 2-(1-hydroxy-2-nonynyl)-3-methyl-4-actoxy- 6-fluoroquinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:31]2[C:26](=[C:27]([CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:26]=4[CH:25]=[N:24][N:23]5[CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][O:17]4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cnn(C3CCCCO3)c2c1
Temperature: 120 °C
Yield: 94.8 %

Procedure:
A tube was charged with 53 (350 mg, 1.47 mmol), 199 (340 mg, 1.47 mmol), and DIPEA (5 mL) in IPA (10 mL), degassed, sealed and heated at 120° C. for 48 h. The solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 600 mg (94%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)pyrimidine-2,4-diamine (200) as yellow solid: MS (ESI) m/z=431.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccnc(Cl)c1
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+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2ccccc2)c1
Yield: 84.4 %

Procedure:
A 1 L round bottom flask was charged with 2-chloro-4-methylpyridine (25 g, 196 mmol), phenylboronic acid (23.9 g, 196 mmol), potassium carbonate (81 g, 588 mmol), Pd(PPh3)4 (2.3 g, 1.9 mmol), dimethoxyethane (500 mL) and water (150 mL). The reaction mixture was degassed with nitrogen and heated to reflux for 22 h. After cooling, the aqueous layer was extracted with EtOAc; the organic portion was combined and subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to give 28 g (78%) of 4-methyl-2-phenylpyridine. The product was confirmed by NMR and GC/MS.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:20][CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:31])=[O:30]
Reactant: OC(CCC(O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The product from Example 207B (2.23 g, 7.12 mmol) and triethylamine (2.98 mL, 21.36 mmol) were combined in dichloromethane (50 mL). The mixture was cooled to −20° C. and methanesulfonyl chloride (1.383 mL, 17.80 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated to give the title product (approx 3.34 g) which was directly used for the next reaction.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:6]1[C:10]2=[C:11]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:9]2[C:8]([CH:27]=[O:28])=[C:7]1[CH3:29])[CH:4]=[CH2:5].O>CO>[CH2:3]([N:6]1[C:10]2=[C:11]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:9]2[C:8]([CH2:27][OH:28])=[C:7]1[CH3:29])[CH:4]=[CH2:5]
Reactant: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCn1c(C)c(CO)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Sodium borohydride (111.2 mg, 2.94 mmol) was added to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-3-formyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (350 mg, 0.98 mmol) prepared in Step 4 in methanol (10 ml). The reaction mixture was stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 100 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]1(=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3](=[O:4])[CH2:2]1.N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([CH2:18][C:17]([CH:2]1[C:1](=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3]1=[O:4])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCc2ccccc2)C(=O)O1
Temperature: 3 °C
Reaction time: 0.05 h
Yield: 97.3 %

Procedure:
To a stirred mixture of isopropylidene malonate (5.00 g, 34.7 mmol) in anhydrous dichloromethane (15 ml), cooled under nitrogen to 3° C., was added dropwise, over 7 min, dried pyridine (6.81 ml, 84.2 mmol). The resulting colourless solution was stirred at 3° C. for 3 min, then a solution of hydrocinnamoyl chloride (5.00 ml, 33.7 mmol) in anhydrous dichloromethane (13 ml) was added dropwise over 2.5 h, whilst maintaining the temperature below 6° C. The resulting orange cloudy mixture was stirred at 3° C. for 1 h, then at room temperature for 2.5 h. The mixture was diluted with dichloromethane (20 ml) and poured into ice-cold 1M aqueous HCl (42 ml). The aqueous layer was further extracted with dichloromethane (2×25 ml), and the combined organic extracts were washed with 1M aqueous HCl (2×25 ml), then saturated aqueous NaCl (25 ml), dried (Na2SO4) and evaporated in vacuo to leave 9.06 g of crude 5-benzylacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione as an orange oil.
Reaction SMILES: O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2:13].[CH2:14]([N:25]([CH2:30][C:31]([OH:33])=[O:32])[CH2:26][C:27]([OH:29])=[O:28])[CH2:15][N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]>>[Fe:13].[CH2:15]([N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[CH2:14][N:25]([CH2:30][C:31]([OH:33])=[O:32])[CH2:26][C:27]([OH:29])=[O:28]
Reactant: [Fe+2]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: [Fe]

Procedure:
A 100X stock solution of iron and EDTA was prepared by dissolving 1.39 g of iron (II) sulfate heptahydrate and 1.86 g of disodium-EDTA in 500 ml of distilled, deionized water.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([OH:18])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC=CC=2C=N1>CN(C=O)C.C(OCC)(=O)C>[CH3:23][C:24]1([CH2:28][O:18][C:15]2[C:14]3[CH:19]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][CH:6]=4)[CH:11]=[CH:12][C:13]=3[O:17][N:16]=2)[CH2:27][O:26][CH2:25]1
Reactant: CC1(CBr)COC1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc2oncc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)COC1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), 3-bromomethyl-3-methyloxetane (150 mg, 0.91 mmol) and cesium carbonate (300 mg) were combined in 5 mL DMF and stirred at ambient temperature until HPLC showed complete disappearance of benzisoxazole starting material. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-60% ethyl acetate in hexane gave the title compound (80 mg, 0.21 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41]([N:45]=[C:46]=[O:47])[CH:42]=[CH:43][CH:44]=1.CO>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:46]([NH:45][C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:48])[F:49])[CH:40]=5)=[O:47])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CN)cc4)cnc3c2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CNC(=O)Nc5cccc(C(F)(F)F)c5)cc4)cnc3c2)cc1
Yield: 65.7 %

Procedure:
Dissolve 4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzylamine (2.37 g, 6.28 mmol) and diisopropylethylamine (2.44 g, 3.28 mL, 18.84 mmol) in dimethylsulfoxide under a nitrogen environment at room temperature. Add 3-trifluoromethylphenylisocyanate (1.17 g, 6.28 mmol) and stir the mixture for 2.5 hours. Pour the reaction contents onto a Varian SCX column (50 g) prewashed with methanol. Wash the column with dichloromethane, 1:1 methanol/dichloromethane and methanol (150 mL each). Elute the title compound with 2 N NH3/methanol (300 mL). Concentrate the methanolic solution to dryness and chromatograph on silica using 0→3→5→10% methanol/dichloromethane over 4, 15 and 30 minutes, respectively. Dissolve the product in heated CHCl3 (65 mL), followed by treatment with hexanes (5 mL) and cooling. Dry the resulting precipitate in vacuo to yield the product (2.33 g, 66%). MS(ES), m/z 565 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:31])[CH:3]=1.F[B-](F)(F)F.[N:37]1(OC(N(C)C)=[N+](C)C)[C:41]2[CH:42]=CC=C[C:40]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH:41]([NH:37][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[F:31])[NH:8][N:7]=3)[N:12]=2)[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:18]=1)=[O:21])([CH3:42])[CH3:40]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (140 mg, 0.30 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (146 mg, 0.46 mmol), N,N-diisopropylethylamine (0.27 ml, 1.52 mmol) and isopropylamine (31 ul, 0.36 mmol) were added together in acetonitrile (1 ml). The reaction was stirred at room temperature for 18 h then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 77 mg (51%) of 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=O)[CH:16]([CH3:18])[CH3:17].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[S:29])[CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Yield: 196.3 %

Procedure:
In a 500 mL three-neck flask were put 20 g (80 mmol) of N-(9H-fluoren-2-yl)isobutyramide, 16 g (40 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), and 150 mL of toluene, and the mixture was heated and refluxed at 130° C. for 4 hours. After that, the precipitated solid was washed with toluene and subjected to suction filtration to give 21 g of a yellow solid of N-(9H-fluoren-2-yl)isobutyrthioamide in a yield of 100%. The synthesis scheme of Step 2 is shown in (c-2) below.