Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1.CO>C1CCCCC1.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:12]2[CH2:13][CH2:14][N:10]([CH3:9])[C:11]2=[O:15])=[CH:19][N:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN1CCC(Cc2ccc(Cl)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere at a temperature of from −78° C. to −60° C., 150 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise in the course of one hour to 20 g of N-methylpyrrolid-2-one in 50 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.0 g of 2-chloro-5-(chloromethyl)-pyridine in 40 ml of THF are added, and the mixture is stirred for a further 6 hours at that temperature and then for a further 6 hours at 0° C. 15 ml of methanol are added and the reaction mixture is then poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over magnesium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant. The title compound (compound 1.4) is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[CH:23][N:22]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:20][C:21]1[CH:26]=[C:25]([C:27]([N:11]([CH3:12])[C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[O:28])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(C(=O)Cl)ccn1
Reactant: CNc1ccc([N+](=O)[O-])c(C)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc([N+](=O)[O-])c(C)c2)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 16.6 g (0.1 mol) of 3,N-dimethyl-4-nitrobenzenamine and 10.2 g (0.1 mol) of triethylamine in mL of methylene chloride cooled to 0° C. under a nitrogen atmosphere add slowly a solution of 15.6 g (0.1 mol) of 2-methylpyridine-4-carbonyl chloride (prepared from the corresponding acid and thionyl chloride) such that the temperature is maintained between 0°-5° C. After the addition is complete, stir the mixture for 6 h and allow to warm slowly to room temperature. Quench the reaction mixture by the addition of 50 mL of water. Separate the layers and wash the organic layer with two 50 mL portions of water, two 50 mL portions of 5% sodium bicarbonate solution and 50 mL of saturated sodium chloride solution. Dry the methylene chloride solution over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[N:23]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:28]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:30])=[O:29])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)N4CCCC4)c3F)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 24.7 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 354 mg, 1.19 mmol) in 9.5 mL of tetrahydrofuran, 0.84 mL of pyridine was added. Pyrrolidine-1-sulfonyl chloride (31, 403 mg, 2.37 mmol) was added and the solution was stirred at 60° C. for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0006, 127 mg). MS(ESI)[M+H+]+=432.1.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=[N:8]1.[CH2:33]1[NH:38][CH2:37][CH2:36][N:35]2[C:39](=[O:42])[CH2:40][CH2:41][CH:34]12.N1NC(C2C=CC(OC3C=C4C(=CC=3)N=C(CN3CCC(N5CCOC5=O)CC3)C=C4)=NC=2)=CC=1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH2:29][N:38]3[CH2:37][CH2:36][N:35]5[C:39](=[O:42])[CH2:40][CH2:41][CH:34]5[CH2:33]3)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(C=O)ccc3c2)nc1
Reactant: O=C1CCC2CNCCN12
Agent: O=C1OCCN1C1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cn4)ccc3n2)CC1
Product: O=C1CCC2CN(Cc3ccc4cc(Oc5ccc(-c6ccn[nH]6)cn5)ccc4n3)CCN12

Procedure:
The title compound 18 is synthesized from intermediate D (0.100 g, 0.224 mmol) and hexahydro-pyrrolo[1,2-a]pyrazin-6-one (78.5 mg, 0.560 mmol) according to the procedure described for the synthesis of compound 11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCNCCCC
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The di-n-butylamine (2.59 g, 0.02 mole) was added and the reaction mixture was heated at 60° C. for 3 hrs.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:8])[C:4](=[NH:7])[CH2:5][SH:6].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[ClH:1].[CH3:2][N:3]([CH3:8])[C:4](=[NH:7])[CH2:5][S:6][C:9](=[O:11])[CH3:10]
Reactant: CN(C)C(=N)CS
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)SCC(=N)N(C)C

Procedure:
To a solution of 1.54 g. of N, N-dimethyl-2-(mercapto) acetamidine hydrochloride in 15 ml. of acetic acid was added 2 ml. of acetic anhydride, and the reaction mixture was heated at 55°-60° C. for 3 hours, after which it was concentrated in vacuo. The product was crystallized from ether, filtered, and air dried, then recrystallized from ethanol to yield 1.1 g., m.p. 162.5°-163° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH3:13]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:17]=[CH:16]/[C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[O:18])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(I)cc1
Reactant: C=CC(=O)OCCCC
Product: CCCCOC(=O)/C=C/c1ccc(C#N)cc1

Procedure:
4-Iodobenzonitrile (57 mg, 0.25 mmol) and n-butylacrylate (54 μL, 0.375 mmol) were coupled using the procedure described above, except the reaction was performed at 50° C., to give 100% conversion to (E)-n-butyl 3-(4-cyanophenyl)acrylate by GC analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C=CC=CC1=O.[CH3:59][C:60]([OH:64])([C:62]#[CH:63])[CH3:61]>>[OH:64][C:60]([CH3:61])([CH3:59])[C:62]#[C:63][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1COc1ccccn1)CCOc1ccc(Br)cc1-2
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: O=c1cccc[nH]1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccn3)n1CCO2
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((pyridin-2-yloxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-pyridone) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (5 mg, 5%).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:8]([O:13]C)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(OCC)(=O)C>[CH:1]1([CH2:6][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ncccc1CC1CC=CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=c1[nH]cccc1CC1CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a cloudy dispersion containing 3-(cyclopent-3-en-ylmethyl)-2-(methyloxy)pyridine (Preparation 28, 2.1 g, 11.1 mmol) and sodium iodide (4.1 g, 27.8 mmol) in anhydrous acetonitrile (25 ml) was added chlorotrimethylsilane (3.0 g, 27.8 mmol). A white precipitate formed which was stirred for 30 min at room temperature and then for 1 h at 70° C. The reaction mixture was cooled to room temperature and water was added, followed by ethyl acetate (200 ml), the organic layer washed with water (4×) and then with sodium hydrogen carbonate solution and brine before drying (Na2SO4) to give the title compound as a yellow solid (1.93 g, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.[Cl:28]C1C=CC=CC=1Cl>CN(C)C1C=CN=CC=1>[Cl:28][C:3]1[C:2]([O:1][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Clc1ccccc1Cl
Reactant: Oc1ccc2ncccc2c1I
Agent: CN(C)c1ccncc1
Product: COc1cc2nccc(Oc3ccc4ncccc4c3Cl)c2cc1OC
Temperature: 120 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
6-Hydroxy-5-iodo-quinoline (100 mg), 4-chloro-6,7-dimethoxyquinoline (215 mg), and 4-dimethylaminopyridine (367 mg) were suspended in o-dichlorobenzene (12 ml), and the suspension was stirred at 120° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 12%).
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.N1(C2SC3C=CC([OH:23])=CC=3N=2)CCNCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[S:48][C:49]3[CH:55]=[CH:54][C:53](O)=[CH:52][C:50]=3[N:51]=2)[CH2:43][CH2:42]1)=[O:40]>FC(F)(F)C(O)=O.CC(O)(C)C>[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[S:48][C:49]3[C:55]([OH:23])=[CH:54][CH:53]=[CH:52][C:50]=3[N:51]=2)[CH2:43][CH2:42]1)=[O:40]
Reactant: O=C(N1CCN(c2nc3cc(O)ccc3s2)CC1)C(F)(F)F
Reactant: Oc1ccc2sc(N3CCNCC3)nc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(N1CCN(c2nc3cccc(O)c3s2)CC1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
The thiourea obtained from the reaction of 3-methoxyphenyl isothiocyanate (5.02 g, 30.4 mmol) with piperazine (13.01 g, 151 mmol) in refluxing t-BuOH was cyclized with K3Fe(CN)6 and subsequently deprotected with molten pyridinium hydrochloride at about 160° C. according to the procedure described for Preparation 84, but without the chromatographic separation of the 5- and 7- isomers. The resulting 2-(piperazinyl)-benzothiazol-5-ol and -7-ol mixture (2.35 g, 10 mmol) was dissolved in trifluoroacetic acid (20 mL) and chilled to about 0-5° C. Trifluoroacetic anhydride (3.4 mL, 24 mmol) was added dropwise over several minutes. After stirring for about 3 h. at about 20° C. the mixture was concentrated in vacuo at about 35° C. and then redissolved in H2O (50 ml) with adjustment of the pH to 6-7 by careful addition of saturated aqueous K2CO3. The mixture was stirred for about 30 min. at about 20° C., diluted with H2O (60 mL) and extracted with 5% MeOH in CH2Cl2 (1×100 mL, 2→40 mL). Pooled organic extracts were dried over Na2SO4 (s) and concentrated in vacuo to afford a mixture of the 2-(4-trifluoroacetylpiperazin-1-yl) benzothiazol-5-ol and -7-ol isomers as a foamy solid (2.12 g; GC-MS m/z 331). The isomers were resolved by flash chromatography on silica (35% EtOAc/hexanes) to yield 820 mg of the pure 2-(4-trifluoroacetyl-piperazin-1-yl)benzothiazol-7-ol as the faster eluting isomer.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:36]2=[O:37])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCN=C=O
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: CCCCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and butyl isocyanate to give the title compound as a colorless solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[C:17](=[O:20])(O)[O-].[Na+].C1(OC(Cl)=O)C=CC=CC=1.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[N:34]1>C1COCC1>[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH:39][C:17](=[O:20])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([B:8]3[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]3)=[CH:4][CH:3]=2)[CH:35]=[N:34]1
Reactant: Cn1cc(CN)cn1
Reactant: O=C([O-])O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CNC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
(4-Aminophenyl)boronic acid pinacol ester (200 mg) was dissolved in dry THF (5 mL) and sodium bicarbonate (116 mg) added followed by the dropwise addition of phenylchloroformate (0.115 mL). The mixture was stirred at RT for 1 hour. (1-Methylpyrazol-4-yl)methanamine (102 mg) was added and the reaction left to stir at RT for 2 h before being heated to 40° C. for 16 h. The mixture was concentrated in vacuo and the residue partitioned between DCM (25 mL) and water (25 mL). The organics were dried over magnesium sulphate, filtered and vacuumed to dryness. The material was chromatographed on silica, eluting with ethyl acetate, to give the desired material (232 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[CH:6][N:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[Cl:12]CCl.C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>N1C=CC=CC=1>[ClH:12].[NH2:1][C:2]1[C:7]([CH2:8][Cl:24])=[CH:6][N:5]=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1ncc(CO)c(N)n1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1ncc(CCl)c(N)n1
Product: Cl
Reaction time: 8 h

Procedure:
4.59 g (0.03 mol) of 4-amino-2-ethyl-5-(hydroxymethyl)-pyrimidine was charged into a 100 ml flask, followed by 20 ml of dichloromethane, 20 ml of toluene and 0.1 ml of pyridine. 6.5 ml of thionyl chloride (0.28 mol) was dropped in slowly with cooling by ice bath. Then the reaction was stirred overnight. Solvent was removed and the residue was used for next step directly.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][CH:14]([C:16]2[N:21]=[N:20][C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[N:18][CH:17]=2)[CH3:15])=O)=[CH:3]1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[N:20]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cn(C)c5ccccc45)n3n2)cc1
Yield: 54 %

Procedure:
Applying the Cyclization Procedure 2, using 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-3-carboxamide (Intermediate 54) (107 mg, 0.26 mmol), pyridine (2.65 mL), 1,2,4 triazole (55 mg, 0.80 mmol) and phosphorus oxychloride (0.037+0.010 mL, 0.50 mmol), to afford 5-methyl-7-(1-methyl-1H-indol-3-yl)-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (54 mg) as a yellow solid. MS m/z 385 (M+1).
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[C:1]1([C:5]([O:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH2:4][CH2:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)C1=CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.3 %

Procedure:
Cyclobut-1-enecarboxylic acid (0.51 mmol, 50 mg) was dissolved in 0.5 ml dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (0.51 mmol, 43 μl) was added. The temperature of the solution was raised to room temperature, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. Phenol (0.51 mmol, 48 mg) and triethylamine (1.02 mmol, 142 μl) were dissolved in 0.5 ml dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing the cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The reaction was quenched with 1 N HCl, and was extracted with CH2Cl2 (30 ml). The CH2Cl2 solution was washed with 5% NaHCO3 (2×10 ml), dried over Na2SO4, concentrated by rotary evaporation, and then purified by flash column chromatography (100% CH2Cl2) to yield 11 as a colorless oil (42 mg, 47%). 1H-NMR (100 MHz) δ 7.42 (m, 2H), 7.28 (m, 1H), 7.14 (m, 2H), 7.02 (s, 1H), 2.88 (t, J=3.0 Hz, 2H), 2.60 (m, 2H). 13C-NMR (400 MHz) δ 160.5, 150.8, 149.2, 138.3, 129.6, 125.9, 121.8, 29.5, 27.7. HRMS (EI) calcd. for C11H10O2 [M]+ 174.0679, found 174.0681.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.[C:19]1([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH2:31][CH2:32][CH2:33]O)[N:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:33][CH2:32][CH2:31][C:28]3[N:27]=[C:26]([CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:30][N:29]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Reactant: OCCCc1noc(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (195 mg, 0.89 mmol) and PPh3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified on a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated by high vacuum and purified on a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh3)4 (61 mg, 0.053 mmol) and morpholine (460 μl, 5.3 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated to leave the title compound as a white solid (36 mg, 11%).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=O)C.[OH-].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[Cl:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:14]1[CH2:13][C:12]2[C@H:7]([CH2:8][CH2:9][C:10](=[O:34])[CH:11]=2)[C@@H:6]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][C@H:5]2[OH:4])([CH3:21])[C:19](=[O:23])[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCCl)CC3=CC(=O)CC[C@@H]3[C@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12C[C@@H](O)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 3 h
Yield: 58.3 %

Procedure:
6.0 g of 11α-acetoxy-7α-(9-chlorononyl)-estr-4-ene-3,17-dione is saponified at 60° C. in a mixture of 12 ml of tetrahydrofuran and 12 ml of methanol with 17 ml of a 1N potassium hydroxide solution. After 3 hours, it is diluted with ethyl acetate, washed neutral with saturated sodium chloride solution and water and dried. The chromatography of the crude product on silica gel with a methylene chloride-acetone gradient yields 3.2 g of 7α-(9-chlorononyl)-11α-hydroxy-estr-4-ene-3,17-dione as an oil.