Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[NH3:29].O1CCOCC1>O>[NH2:29][C:7]1[C:2]([Br:1])=[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])[N:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:6]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Reaction time: 48 h
Yield: 40.4 %

Procedure:
4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (0.00250 mol) and NH3/1,4-dioxane 0.5M (0.015 mol) were heated in a pressure vessel at 150° C. for 4 days. The sample was allowed to sit at ambient conditions for 2 days. Water was added slowly to the mixture until a precipitate formed. The mixture was stirred for 2 hours and filtered. The solid was recrystallized from CH3CN to obtain 0.58 g (fraction 1). The filtrate was evaporated (fraction 2). Both fractions were combined and purified by column chromatography, eluting with CH2Cl2. The resulting residue of the desired fraction was recrystallized from CH3CN to yield 0.44 g of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile (40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (interm. 30). 4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile (interm. 31) was prepared according to an analogous procedure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[CH:5]=1.P(Cl)(Cl)([Cl:13])=O>ClCCl>[Cl:13][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)ncn1
Solvent: ClCCl
Product: COCc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 76.9 %

Procedure:
6-(Methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol) was taken up in dichloromethane (14 ml) and phosphorous oxychloride (9 mL, 97 mmol) was added at ambient temperature. The mixture was stirred at ambient for 18 h and concentrated. The residue was taken up in ice-water and the pH was adjusted to 7 with 1N sodium hydroxide. The mixture was extracted with chloroform and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (5-10% ethyl acetate/chloroform) to afford 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol, 77% yield) as a pale yellow oil, which solidified on standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1 H, d, J=1.01 Hz), 7.52 (1 H, d, J=1.01 Hz), 4.53 (2 H, s), 3.50 (3 H, s). MS (LC/MS) R.T.=0.98; [M+H]+=159.10.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[CH:9][CH:10]=1)=[O:18]
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 6 °C
Reaction time: 2 h

Procedure:
A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (≦0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5% “as-is” yield).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11])([O-:6])=[O:5].C(OCC)(=O)C>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dimethylamine (50% aqueous solution, 3.6 ml) was stirred in an ice bath and a solution of 3-nitrobenzoyl chloride (1.8 g) in 1,4-dioxan (4 ml) was dropwise added thereto. The resulting mixture was stirred vigorously at ambient temperature for 2.5 hours. Ethyl acetate was added and organic layer was washed with water, 1N hydrochloric acid, 1N sodium hydroxide, water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was recrystallized from benzene-n-hexane to afford N,N-dimethyl-3-nitrobenzamide (1.5 g) as a pale yellow prism.
Reaction SMILES: COC1C=CC(B2[O:13][C:12](C)(C)[C:11]([CH3:17])([CH3:16])O2)=CC=1CS(N)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C1(C(Cl)=O)CC1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([C:12]([N:51]2[CH2:52][CH2:53][N:48]([C:45]3[CH:46]=[CH:47][C:42]([C:39]4[CH:40]=[C:41]5[C:33]([C:31]6[CH:30]=[N:29][N:28]([CH2:27][C:26]7[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=7)[CH:32]=6)=[CH:34][N:35]([S:54]([C:57]6[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=6)(=[O:56])=[O:55])[C:36]5=[N:37][CH:38]=4)=[CH:43][N:44]=3)[CH2:49][CH2:50]2)=[O:13])[CH2:17][CH2:16]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was acylated with cyclopropane carbonyl chloride (22 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=676.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:32]([C:33]#[N:34])=[C:17]4[N:18]=[CH:19][CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=5)[N:16]4[N:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:36]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:32]([C:33]([NH2:34])=[O:36])=[C:17]4[N:18]=[CH:19][CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=5)[N:16]4[N:15]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 7.0 g of 2-[4-(phenylmethyl)-1-piperazinyl]-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Example 24) and 50 ml of concentrated sulfuric acid was stirred at room temperature for 5 hours. The yellow solution was poured into ice/water. The precipitate formed was collected and washed with water, then dried in vacuo. The material was recrystallized from acetonitrile, collected and dried and gave 4.8 g of the product of the Example as a yellow solid, mp 252°-254° C.
Reaction SMILES: [F:1][C:2]([S:5]([NH2:8])(=[O:7])=[O:6])([F:4])[F:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([NH:8][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)=[O:23])(=[O:7])=[O:6]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of trifiuoromethylsulphonamide (2.1 g, 14.1 mmol) in anhydrous dichloromethane (50 ml), cooled to 0° C. was treated with triethylamine (2.0 ml, 14.1 mmol) followed by a solution of 3-nitrobenzoyl chloride (2.5 g, 13.4 mmol) in anhydrous dichloromethane (50ml) dropwise. After stirring at 0° C. for 1h, the mixture was stirred at ambient temperature for 2 h. The mixture was extracted using 1M NaOH (100 ml), and the aqueous phase was acidified using 5M HCl. The aqueous phase was then extracted using dichloromethane (4×100 ml), followed by ethyl acetate (2×100 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to leave a yellow solid. This was recrystallised from diethyl ether:hexane (1:1) to afford the title compound (1.5 g, 36%) as a pale yellow solid. mp 80°-83° C. 1H NMR (360 MHz, D6 -DMSO) δ 7.73 (1H, dd, J=8.0 and 8.0 Hz), 8.35 (2H, m), 8.56 (1H, brs), 8.68 (1H, m).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[NH:10][C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[H-].[Na+].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22]
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(Br)c4c3c2)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(c2)c2c(Br)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (547 mg, 1.55 mmol) in DMF (25 ml) under a flow of nitrogen was added sodium hydride (93 mg, 60% dispersion in mineral oil, 2.39 mmol). After 20 min, a yellow solution had formed and (2-chloromethoxyethyl)-trimethyl-silane (358 μL, 2.02 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 days, then diluted with water and sonicated. The resultant solid was collected by filtration and triturated with methanol to afford the title compound as a yellow solid (404 mg, 54%). 1H NMR (CDCl3, 300 MHz): δ 9.13 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.83-7.77 (m, 1H), 6.06 (s, 2H), 4.06 (s, 3H), 3.70-3.59 (m, 2H), 1.03-0.92 (m, 2H), -0.03 (s, 9H).
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>O>[C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: N[C@@H]1CCNC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: N[C@H]1CCNC1
Temperature: 80 °C

Procedure:
To the filtrate obtained in the above crude (3R)-3-aminopyrrolidine D(-)-tartrate is added a solution of L(+)-tartaric acid (25 g) in water (50 ml), and the precipitated crystals are separated by filtration. The product is dissolved in a 20% aqueous sodium hydroxide solution (50 ml) and thereto is added acetone (300 ml), and the precipitated crystals are removed by filtration. To the filtrate is added a solution of L(+)-tartaric acid (20 g) in water (40 ml). The precipitated crystals are separated by filtration and dissolved in water (30 ml), and thereto is added sodium hydroxide (300 g). The mixture is extracted with ether (300 ml) three times. Ether is distilled off under reduced pressure, and to the residue is added a solution of L(+)-tartaric acid (5.5 g) in water (25 ml), and the mixture is heated at 80° C. To the mixture is added methanol (40 ml), and the mixture is gradually cooled till room temperature. The precipitated crystals are separated by filtration and recrystallized from a mixed solvent of methanol:water (1:1) to give (3S)-3-aminopyrrolidine L(+)-tartrate (5.0 g).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]([CH3:31])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[N:23]([CH3:31])[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH2:11]2)=[O:7])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: Cn1c(C(=O)NCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)cc2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)c2cc3ccccc3n2C)C1

Procedure:
N-(4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-methyl-1 H-indole-2-carboxamide (0.95 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.45 g) to give N-(4-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:24])[C:6]([CH3:11])=[C:5]2[S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: CI
Reactant: Cc1[nH]c2ccc(Cl)cc2c1Sc1cccc(CC(=O)O)c1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2cc(Cl)ccc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [3-(5-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>CCCCC.O1CCCC1>[I:29][CH2:30][CH2:31][CH2:32][C:33]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34]
Reactant: O=C(Cl)CCCI
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCI)c1coc([Si](C)(C)C)c1
Reaction time: 0.25 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.33 ml, 0.56 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (188.1 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at 0° under argon. After 15 minutes, a solution of 4-iodobutyryl chloride (129 mg, 0.56 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued overnight while the cooling bath attained room temperature. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts afforded an oil, which was purified by preparative TLC (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:12][C:13]([CH3:21])([CH3:20])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18]Br.C(OCC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH:4](/[CH:18]=[CH:17]/[CH2:16][C:15]#[C:14][C:13]([CH3:21])([CH3:20])[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)C#C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(/C=C/CC#CC(C)(C)C)C(=O)OC
Reaction time: 1 h

Procedure:
4.05 ml of malonic acid dimethyl ester is dissolved in 40 ml of dimethylformamide, 1.29 g of 60% oily sodium hydride and 6.5 g of (E)-6,6-dimethyl-2-hepten-4-ynyl bromide (containing about 5% Z-form) are added gradually, and the mixture is stirred at that temperature for 1 hour. Saturated saline and ethyl ether are added to the reaction solution to form two liquid phases, the ether layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [Wako gel C-200, 400 g; hexane/ethyl acetate=19/1→9/1] to obtain 6.26 g of (E)-6,6-dimethyl-2-hepten-4-ynylmalonic acid dimethyl ester as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:25][C:26]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[NH:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:30][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[N:28][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)NC(=N)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=NC(=O)OCc1ccccc1)N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 31.8 %

Procedure:
To the solution of the crude dione 15 (0.10 g, 0.346 mmol) in 25 ml of dry CHCl3 was added N-(benzyloxycarbonyl)-N′-isopropylguanidine (16) (0.122 g, 0.519 mmol) at room temperature. The reaction mixture was heated at 50° C. for 18 hours and then quenched with water. The mixture was extracted with chloroform and dried over Na2SO4. The CHCl3 was removed in vacuo and the crude product was recrystallized from hexanes/CHCl3 to yield compound 4d as light yellow crystals (51 mg, 0.11 mmol, 31%), mp 211° C. 1H NMR (300 MHz, CDCl3): δ 7.54–7.51(m, 2H), 7.41 (s, 5H), 7.25 (dd, J=8.6 and 2.4 Hz, 1H), 5.25 (s, 2H), 4.12 (m, 1H), 2.46 (d, J=6.6 Hz, 6H). 13C NMR: δ 170.83, 155.86, 153.87, 133.89, 132.56, 132.19, 131.22, 130.42, 129.21, 128.93, 128.65, 128.61, 125.60, 69.24, 45.25, 22.28. MS (m/z): 476 (M+), 370, 316, 314, 236. Anal. (C21H19Cl2N5O4) C, H, Cl, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5](O)=[O:6].[CH3:13][Si:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].Cl.CN(C)CCCN=C=NCC.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5]([NH:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(CBr)c(Br)c1
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
3-bromo-4-(bromomethyl)benzoic acid (5 g), 1-(trimethylsilyl)methylamine (1.76 g), N,N-dimethylaminopyridine (0.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g) were dissolved in dichloromethane (30 ml), and stirred for 5 hours at room temperature. Water was added to the reaction mixture, and then organic layer was separated and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1.Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2cc3ccccc3cc2F)n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(NCc2ccc(C#N)cc2)n(-c2cc3ccccc3cc2F)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To the mixture of 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (200 mg, 0.48 mmol) and 4-bromomethylbenzonitrile (140 mg, 0.72 mmol) in 5 mL DMF was added Cs2CO3 (234 mg, 0.72 mmol). The mixture was stirred for overnight at 50° C. It was diluted with 200 mL EtOAc, washed with water ×2, dried, evaporated in vacuuo, purified using flash column to afford 3-methyl-1-(3-fluoro-2-naphthyl)-5-((4-cyanophenyl)methylamino)-1H-pyrazole. ES-MS: (M+H)+357.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Br)c1
Reaction time: 1 h

Procedure:
A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47 mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to beige solids (1.25 g, 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[NH2:10][C:11]1[CH2:12][C:13]([C:29](OCC)=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:10][C:11]1[CH2:12][C:13]([C:29]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[CH:18][C:16]=2[N:17]=1
Reactant: COCCNCCOC
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminuni (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).