Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[N:34]1([CH2:39][CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:38]=[CH:37][N:36]=[N:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnn1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCn4ccnn4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 66.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.25 g, 0.54 mmol), 4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.31 g, 0.54 mmol) to give the title compound: Rf=0.41 (silica gel, 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4]1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>ClCCl>[C:23]([NH:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN)C1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CNC(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Into a 50 mL round bottom flask was added 15S (820 mg, 2.68 mmol) and dichloromethane (15 mL). Benzoic acid (15T) (426 mg, 1.3 eq) and EDC (669 mg, 1.3 eq) was added and the flask was cooled to 0° C. DIEA (1.04 g, 3 equiv.) was slowly added and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by column chromatography with 5% methanol in dichloromethane to give 15U as a solid (865 mg, 79%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[CH2:12][CH2:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[C:7]2[CH2:12][CH2:11][NH:10][C:8]=2[N:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2CC2)nc2c1CCN2
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc(C2CC2)nc2c1CCN2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ol 48 (0.5 g, 2.8 mmol) is suspended in phosphorus oxychloride (0.7 ml). A mixture of N,N-diethylaniline (0.46 g, 3.1 mmol) and phosphorus oxychloride (0.7 ml) is added dropwise to the suspension at room temperature. The resulting mixture is stirred at 120° C. for 3 h. The solution is poured onto crushed ice and extracted two times with dichloromethane. The aqueous layer is alkalinized (pH 10) and extracted four times with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude mixture (370 mg, 68%, 91% purity) is used in the next step without further purification due to the unstability of the compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:25][O:26][CH2:27]Cl>>[CH3:25][O:26][CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: COCCl
Product: COCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 102.7 %

Procedure:
In a similar manner to Example 10(b), by reaction of 3 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde [prepared in Example 16(a)] with 777 μl (10.2 mmol) of methoxymethyl chloride, 3.5 g (100%) of the expected product are obtained in the form of an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:27])[C:18]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl.O>C(O)(=O)C>[Cl:27][C:17]1[C:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Yield: 34.4 %

Procedure:
1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.361 g) was dissolved in glacial acetic acid (9 mL) and 6N HCl (9 mL) and heated in a sealed tube at 100° C. for 6 h. After cooling in ice, water (5 mL) was added and the solids were collected via filtration, washed with water, and dried under vacuum (60° C., 10 mmHg). The resulting tan powder was recrystallized from MeOH:water (10 mL, 10:1), collected via filtration and dried under reduced pressure to afford the title compound as a tan solid (115 mg, 90%). Mp=134-138° C. (dec.). MS (ESI/CI): mass calcd. for C17H11ClN4O3, 354; m/z found, 355 [M+H]+, 396 [MH+MeCN]+. 1H NMR (mixture of tautomers) (500 MHz, DMSO-d6): 13.60 (s, 0.5H), 13.50 (s, 0.5H), 12.93 (s, 1H), 8.89 (s, 1H), 8.30 (s, 1H), 7.90 (s, 0.5H), 7.65 (s, 0.5H), 7.42 (m, 2.5H), 7.15 (m, 1.5H), 7.02-6.75 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Yield: 17 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (192 mg, 0.61 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (136 mg, 0.60 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (55 mg, yield: 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)cc1
Yield: 81.4 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 4-methoxyphenyl isocyanate (0.0098 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (24.8 mg, 81%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.40-7.45 (m, 3H), 7.33-7.36 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.06 (t, J=7.6 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.85-6.88 (m, 2H), 4.22 (dt, J=12.6, 3.5 Hz, 1H), 3.69-3.75 (m, 4H), 3.50-3.58 (m, 2H), 2.92-2.99 (m, 1H).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([CH3:20])[CH:19]=2)=[C:9]([F:27])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]#[CH:36]>O>[Cl:6][C:7]1[C:12]([O:13][CH2:36][C:35]#[CH:34])=[CH:11][C:10]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:22])([F:23])[F:24])=[C:18]([CH3:20])[CH:19]=2)=[C:9]([F:27])[CH:8]=1
Reactant: Cc1cc(-c2cc(O)c(Cl)cc2F)c(=O)n(C)c1C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2cc(C)c(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To 10 ml of DMF, 0.20 g (0.6 mmol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,5-dimethyl-6-trifluoromethyl-2(1H)-pyridone, 0.1 g (0.7 mmol) of potassium carbonate and 0.1 g (0.8 mmol) of propargyl bromide were added, followed by stirring at 60° C. for 2 hours. This reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.12 g of the desired product (yield: 53%). Melting point: 107-108° C.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Na+]>C(O)C>[CH3:9][C:2]([N+:10]([O-:12])=[O:11])([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CCC(=O)O)[N+](=O)[O-]
Reaction time: 24 h
Yield: 93.9 %

Procedure:
Methyl 4-methyl-4-nitropentanoate (5.00 g) was dissolved in ethanol (25 ml), and 1 N sodium hydroxide solution was added thereto and stirred for 1 day. The mixture was concentrated under reduced pressure, then chloroform and water were added thereto, and the aqueous phase was washed with chloroform. 2 N Hydrochloric acid (20 ml) was added to the aqueous phase which was then extracted with chloroform, and the extract was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give 4-methyl-4-nitropentanoic acid (4.32 g, Y.:94%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1>>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: FC1(F)CNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC(F)(F)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 3,3-difluoroazetidine to give 221. MS: (ESI+)=389.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].O>O1CCCC1>[Br:1][C:2]1[C:3]([F:8])=[C:4]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1Br
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)c1F)C(F)(F)F
Yield: 30.7 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (5.0 g, 28.6 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at −78° C. was added lithium diisopropylamide (2.0 M in hexane, 15.7 ml, 31.4 mmol). The mixture was stirred for 5 minutes after which ethyl trifluoroacetate (3.76 ml, 31.4 mmol) was added and the stirring was continued at −78° C. for an additional hour. The reaction mixture was brought to ambient temperature and water (50 ml) was added. The phases were separated and the aqueous phase extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (2.38 g). MS m/z (relative intensity, 70 eV) 272 (M+, 11), 270 (M+, 11), 203 (97), 201 (bp, 173 (46).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[O:9]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10]1>CN(C=O)C.C1(C)C=CC=CC=1>[O:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:16])=[CH:10]1
Reactant: O=C=Nc1ccoc1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1ccoc1
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a stirred mixture of 18.3 g (162 mM) of creatinine in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65° C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from ethyl acetate. The solid was then chromatographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 g of the above urea as a tan solid, m.p. 179°-181° C. (dec.).
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].[CH:14]1([N:20]=[CH:21][C:22]([CH3:30])=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Mg]>C1COCC1>[CH:3]1([Ti:13]2([CH:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22]([CH3:30])=[CH:21][N:20]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: [Ti+2]
Reactant: CC(C=NC1CCCCC1)=Cc1ccccc1
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=CN(C2CCCCC2)[Ti](C2C=CC=C2)(C2C=CC=C2)C1c1ccccc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 5.00 g (20.08 mmol) titanocene dichloride in 100 ml THF were added 4.57 g (20.08 mmol) 1-cyclohexyl-3-methyl-4-phenyl-1-aza-buta-1,3-diene and 0.83 g magnesium and the mixture was stirred at room temperature until the metal was fully reacted. The solvent was then removed to dryness in vacuo and the residue was extracted with 50 ml diethyl ether. 5.31 g 2,2-bis(cyclopentadienyl)-1-cyclohexyl-4-methyl-3-phenyl-1-aza-2-titana-cyclopent-4-ene were isolated from the diethyl ether extract as black crystals. (65% yield, characterised by 1H-NMR, 13C-NMR and elemental analysis).
Reaction SMILES: [CH:1]([NH:4][NH2:5])([CH3:3])[CH3:2].[C:6](=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)(Cl)Cl.[CH3:17][O:18][P:19](Cl)([O:21][CH3:22])=[S:20]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[CH3:6][N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][P:19]([O:21][CH3:22])([O:18][CH3:17])=[S:20]
Reactant: CC(C)NN
Reactant: O=C([O-])[O-]
Reactant: COP(=S)(Cl)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COP(=S)(NN(C)C(C)C)OC
Yield: 30.6 %

Procedure:
A mixture of isopropylhydrazine (7.42 g, 0.1 mole), potassium carbonate (20.73 g, 0.15 mole) and triethylbenzyl ammonium chloride (0.3 g, 0.0013 mole was stirred vigorously at reflux with dichloromethane (100 ml) and carbon tetrachloride (60 ml) for 30 minutes. A solution of dimethylchlorothiophosphate (16.6 g, 0.1 mole) in dichloromethane (20 ml) was then added dropwise to this refluxing mixture and the mixture stirred and refluxed for an additional 20 hours. The mixture was then filtered and the filtrate dried over anhydrous magnesium sulfate. The dried filtrate, then was evaporated down to a viscous oil which was subjected to high vacuum for 2 or 3 hours to yield 6.5 g of a thick yellow oil, nD25° =1.5132, identified as the product by NMR, IR and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1>C(N)CN>[NH2:14][CH2:15][CH2:16][NH:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccccc2)n1
Solvent: NCCN
Product: CC(=O)NCCNc1cc(NCCN)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 164.6 %

Procedure:
N-{2-[(6-Chloro-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (100 mg) was dissolved in ethylenediamine (5 ml) and the stirred under reflux for 4 hrs. The reaction mixture was then cooled to ambient temperature and the solvent removed in vacuo. Purification via flash chromatography on silica gel eluting first with a mixture of ethyl acetate and methanol (9:1 v/v) then a mixture of ethyl acetate, methanol and ammonium hydroxide (80:20:2 v/v/v) to furnish the title compound (89 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]1([N:20]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]2)[C:12]2[N:13]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:11]3[C:12]4[N:13]([CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:15][N:16]=3)[CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (2.0 g, 9.9 mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (2.7 g, 9.9 mmol, 1 eq) in 20 mL of DMSO was added triethylamine (5.4 mL, 39 mmol, 3.9 eq) and HATU (4.1 g, 11 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by silica gel flash chromatography (EtoAc:MeOH 2:3) to produce (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (5.0 g, 1.3 mmol, 13%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1Br.[Cu](C#N)[C:14]#[N:15].N.[CH3:19][N:20](C)C=O>>[C:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:19]#[N:20])#[N:15]
Reactant: N#C[Cu]C#N
Reactant: COc1cc(Br)c(Br)cc1OC
Reactant: CN(C)C=O
Agent: N
Product: COc1cc(C#N)c(C#N)cc1OC
Yield: 58 %

Procedure:
A mixture of 106 g (0.36 mols) of 1.2-dibromo-4.5-dimethoxy-benzene, 98 g (1.06 mols) of copper cyanide and 300 ml of dimethylformamide is brought to reflux for five hours, then the mixture is cooled and is poured into 500 ml of 30% ammonia. The residue is again mixed for 10 minutes, then is filtered and washed with water and dried. The product is extracted by ether for 24 hours by using a Soxhlet device and the solvent is evaporated. Thus, 40 g of 1.2-dicyano-4.5 dimethoxybenzene is obtained in the form of white flakes, which corresponds to a yield of 58%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])[CH3:32]>>[CH3:32][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH:37]/[C:19](=[C:6]1\[C:5](=[O:29])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=2)/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:30]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Product: CN(C)Cc1cccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)c1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)[CH:11]=3)=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:38]([O-])=[O:39])C=1.[CH:41]1([CH:44]([OH:46])[CH3:45])[CH2:43][CH2:42]1>N1C=CC=CC=1.O.C(Cl)Cl>[CH:41]1([CH:44]([O:46][C:38](=[O:39])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:25]4[CH2:27][CH2:26]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)[CH:11]=4)=[CH:4][CH:3]=2)[CH3:45])[CH2:43][CH2:42]1
Reactant: CC(O)C1CC1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(OC3CCCO3)ccc12
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC4CCCO4)cc3n2C2CC2)cc1)C1CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (36 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (32 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5](Cl)[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccc2sc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(Br)cc23)CC1
Temperature: 100 °C
Reaction time: 144 h
Yield: 24.8 %

Procedure:
2-Bromo-4-chlorothieno[3,2-c]pyridine (5.0 g, 20.24 mmol) and K2CO3 (13.97 g, 101.2 mmol) was stirred in DMSO (20 mL) followed by addition of tert-butyl piperazine-1-carboxylate (4.14 g, 22.26 mmol). The reaction mixture was stirred at 100° C. for 6 days. The reaction mixture was filtered to eliminate the carbonate and addition of water (50 mL) and ethyl was followed. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 2 g of the desired product, yield 25%, 99% pure. 1H NMR (270 MHz, CDCl3) δ 1.48 (s, 9H), 1.52-1.63 (m, 1H), 3.42-3.47 (m, 4H), 3.61-3.64 (m, 4H), 7.22 (dd, J=5.4, 1 Hz, 1H), 7.35 (d, J=1 Hz, 1H), 8.04 (d, J=5.4 Hz, 1H). m/z=398.91 (M+H), bromide pattern.