Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)[Cl:31]>>[Cl:31][CH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1C
Reactant: ClC(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1nccnc1CCl
Yield: 52 %

Procedure:
Methyl 3-methylpyrazine-2-carboxylate (2.44 g, 16 mmol) was dissolved in chloroform (100 ml) and N-chlorosuccinimde (2.14 g, 16 mmol) was added thereto. Then, benzoyl peroxide (110 mg, 70%, 0.32 mmol) was added and refluxed under heating for 30 hours. The reaction solution was cooled, followed by removing undissolved substance by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1) to obtain 1.55 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1.CC1C=NC=C(C)C=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1)[CH:10]=3
Reactant: Cc1cncc(CCl)c1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cc1cncc(C)c1
Product: Cc1cncc(COc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)c1
Yield: 10 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 3-chloromethyl-5-methylpyridine synthesized from 3,5-dimethylpyridine (500 mg) to obtain the title compound (180 mg; 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Cl
Temperature: 70 °C
Yield: 68.4 %

Procedure:
To a solution of 2-chloro-4-fluoro-1-nitrobenzene (500 mg, 2.85 mmol) in MeCN (10 mL) was added morpholine (0.62 mL, 7.12 mmol) and potassium carbonate (394 mg, 2.85 mmol). The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to afford the title compound (473 mg, 68%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1.[C:32](#[N:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH3:29][N:21]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:39]=[C:19]1[C:18]1[CH:30]=[CH:31][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: -40 °C
Reaction time: 10 h
Yield: 16.5 %

Procedure:
To a solution of diisopropylamine (0.16 mL, 1.1 mmol) in THF at −78° C. was added n-butyllithium (0.38 mL of 2.5 M solution, 0.95 mmol). To the resulting mixture was added a solution of 4-methoxy-N-methyl-N-(4-picolyl)benzamide (0.16 g, 0.62 mmol) in THF. The resulting dark red solution was warmed to −40° C. and stirred for 15 min, at which time benzonitrile (0.13 mL, 1.2 mmol) was added. The mixture to warmed to rt and stirred for 10 h. Aqueous NH4Cl (0.5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material which was isolated was triturated with Et2O and recrystallized from EtOAc to provide the title compound as an off-white solid (35 mg, 17%): mp 193-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:9]1[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1cc(C(C)C)ccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])O)[C:5]([Cl:18])=[CH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.[Na+]>ClCCl.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: OC(c1cc(Cl)ncc1Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(Cl)ncc1Cl)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
The (2,5-dichloro-4-pyridyl)(2,6-difluorophenyl)methanol (744 mg, 2.57 mmol) obtained in Referential Example 53 was suspended in dichloromethane (6 ml), followed by the addition of thionyl chloride (0.5 ml) and dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture was added thionyl chloride (1.0 ml) further. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated. The residue thus obtained was neutralized with a saturated solution of sodium bicarbonate and then, extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue thus obtained was dissolved in dimethylformamide (10 ml). After the addition of sodium 4-chlorobenzenesulfinate (613 mg, 3.08 mmol), the resulting mixture was heated at 50° C. for 5 hours and then, 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated. The resulting solid was recrystallized from diethyl ether-hexane to give the title compound (761 mg, 1.69 mmol, 66%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[CH3:8].IC1C=CC=CC=1CCN.CC(OC(C)=O)=O>O1CCOCC1>[I:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:8]
Reactant: CC(=O)NCCc1ccccc1I
Agent: NCCc1ccccc1I
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: CC1=NCCc2c(I)cccc21
Temperature: 25 °C

Procedure:
N-(2-iodophenethyl)acetamide. A solution of 2-(2-iodophenyl)ethanamine (13.5 g, 54.6 mmol) and Ac2O (10.3 mL, 109 mmol) in 1,4-dioxane (200 mL) was heated to 100° C. for 45 min. The reaction was then allowed to cool to RT and concentrated in vacuo. The resulting residue was taken up in DCM and washed with a saturated aq. solution of NaHCO3— gas formation! The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow oil (16.2 g) which was used as it is in the next step. UPLC-MS: MS 290.3 (M+H+); UPLC rt 0.96 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[C:4]([CH3:11])[N:3]=1.[CH:12]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[C:15]([CH3:16])[C:13]=1[OH:14].CC([O-])(C)C.[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][O:14][C:13]2[CH:12]=[C:19]([CH:20]([CH3:21])[CH3:22])[CH:18]=[CH:17][C:15]=2[CH3:16])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: Cc1nc(Cl)nc(Cl)c1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (17.4 g, 82.7 mmol) and carvacrol (6.21 g, 41.4 mmol) in DMA (166 mL) at 0° C. under nitrogen with magnetic stirring is added KOtBu (42 mL of 1 M in THF, 42 mmol) in dropwise fashion over 20 min. The resulting redish-orange colored solution is allowed to slowly warm to ambient temperature (˜2 h) and stir for 18 h. The reaction mixture is re-cooled to 0° C. and another portion of carvacrol is added (6.21, 41.4 mmol) followed by dropwise addition of KOtBu (42 mL of 1 M in THF, 42 mmol). The reaction mixture is allowed to slowly warm to ambient temperature (˜2 h) and stir for 18 h. The reaction mixture is partitioned between EtOAc (200 mL) and water (60 mL), the organic layer is separated, washed with water (60 mL×3), brine (60 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain an orange oil. The crude product is dissolved in hexanes (300 mL), quickly extracted with Claisen's alkali (50 mL×2), dried over sodium sulfate, filtered and evaporated to obtain an orange oil. Purification by chromatography on silica gel (10 EtOAc/Hexanes) provides the title compound as a colorless oil that solidifies on standing. LC/MS (Method 3), M+H=325.2, Rt=3.03 min.; 1H NMR (CDCl3) δ=7.09 (d, 1H), 6.82 (d, 1H), 6.81 (s, 1H), 5.17 (s, 2H), 2.90 (m, 1H), 2.68 (s, 3H), 2.14, (s, 3H), 1.26 (d, 6H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33][O:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:37][CH2:36][CH2:35][O:34][CH3:33])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: COCCO
Product: COCCOc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CC(F)(F)C3)C2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and 2-methoxyethanol. White solid (37%). MS (EI): 546.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1I.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])[CH2:26][CH2:25]2)=[O:23])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1cnccc1I
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCNCC2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccncc3F)CC2)CC1
Yield: 35.6 %

Procedure:
To a suspension of 3-fluoro-4-iodopyridine (2.23 g), 1-(tert-butoxycarbonyl)-4-(piperidin-4-ylcarbonyl) piperazine (1.49 g) and sodium t-butoxide (1.06 g) in 1,4-dioxan (20 ml) was added tris(dibenzylidene acetone)dipalladium(0) (0.09 g) and tri-o-tolylphosphine (0.12 g) and the mixture heated at reflux for 3 hours. The mixture was diluted with diethyl ether and washed with saturated aqueous sodium chloride solution. dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) eluting with 0.4% methanol in dichloromethane to give as a solid, 1-(tert-butoxycarbonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.70 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[CH:33][CH:32]=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=CC=C(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-dichlorobenzophenone (25.1 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (144 mL), acetaldehye N-tertbutylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 24.0 g of essentially pure 3,3-bis(3-chlorophenyl)-2-propenal as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[NH:14][C@@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[NH:14][C@@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CNC1

Procedure:
To a solution of the compound (1.27 g), which had been obtained in (1), in anhydrous dichloromethane (6 ml), trifluoroacetic acid (3 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][CH2:24][OH:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd]>[OH:25][CH2:24][CH2:23][C:19]1[N:18]([CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:22]=[CH:21][N:20]=1
Reactant: OCCc1nccn1CCCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: OCCc1nccn1CCCc1ccc(O)cc1
Yield: 99.9 %

Procedure:
Using 2-(1-{3-[4-(benzyloxy)phenyl]propyl}-1H-imidazol-2-yl)-1-ethanol (2.53 g) and 10% palladium carbon (0.38 g), the same reaction as Reference Example 11-(v) was carried out to yield the titled compound (1.85 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:18]5[C:19](O)=[N:20][CH:21]=[N:22][C:23]=5[S:24][C:25]=4[C:13]=3[CH:12]=[N:11]2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:19]1[N:20]=[CH:21][N:22]=[C:23]2[C:18]=1[C:17]1[CH2:16][CH2:15][C:14]3[N:10]([CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:11]=[CH:12][C:13]=3[C:25]=1[S:24]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(O)c23)CC1
Product: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(Cl)c23)CC1
Temperature: 105 °C
Yield: 71.4 %

Procedure:
A suspension of 3-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene-6-ol (2 g, 5.4 mmol) in POCl3 (18 ml, 194 mmol) was heated at 105° C. (bath temperature) for 3 h. Analytical HPLC showed no more starting material and a new peak. Excess POCl3 was removed under vacuum and the residue was neutralized with 1N NaOH, extracted with CHCl3:isopropanol (v/v, 3/1). The organic phase was washed with brine, dried over Na2SO4, concentrated to afford a brown syrup, which was purified by silica gel column (CH2Cl2/2N NH3 in MeOH=100/8). The desire product was obtained as a light yellow solid (1.5 g, 71%). 1H-NMR (CD2Cl2-d2) δ 8.66 (s, 1H), 7.60 (s, 1H), 4.19 (t, 2H, J=6.2 Hz), 3.55 (t, 2H, J=8.5 Hz), 3.10 (t, 2H, J=8.3 Hz), 2.80 (t, 2H, J=6.0 Hz), 2.52-2.39 (b, 8H), 2.25 (s, 3H); LCMS RT=1.97 min; [M+H]+=389.4.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][N:10]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1)[C:11](=[O:16])[CH2:12][CH2:13][S:14][CH3:15].C(N(CC)CC)C.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:9][N:10]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1)[C:11](=[O:16])/[CH:12]=[CH:13]/[S:14][CH3:15]
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS/C=C/C(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 40.2 %

Procedure:
N-Chlorosuccinimide (100 mg, 0.75 mmol, 1.1 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (200 mg, 0.68 mmol, 1.0 equiv) in benzene (3.3 mL) at 23° C. The resulting cloudy yellow solution was stirred at 23° C. for 30 m. Triethylamine (210 μL, 1.5 mmol, 2.2 equiv) was added and the resulting bright yellow mixture was stirred at 23° C. for 24 h. The reaction mixture was directly subjected to silica gel column chromatography (ethyl acetate) to afford the title compound as a tan powder (80 mg, 40%): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 8.67 (m, 1H), 8.27 (m, 1H), 8.11 (d, J=14 Hz, 1H), 7.41 (m, 1H), 6.30 (d, J=14 Hz, 1H), 3.91 (s, 3H), 2.46 (s, 3H); ESIMS m/z 293 ([M+H]+).
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]([OH:13])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]>O.C1C=CC=CC=1>[CH3:12][C:4]1([CH3:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][CH2:1][O:13]1
Reactant: CC(C)(O)c1ccccc1N
Reactant: C=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCNc2ccccc21
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
An 8.25-ml solution of 37% aqueous formaldehyde (0.099 mol) was added over 5 minutes to a cooled (0° C.) mixture of 10 g (0.066 mol) α,α-dimethyl-2-aminobenzyl alcohol in 50 ml water. The reaction mixture was then diluted with 50 ml benzene and vigorously stirred for 5 minutes. The aqueous layer was separated and extracted with benzene. The benzene layer of the reaction mixture and the benzene extracts were combined, dried over magnesium sulfate and evaporated. The resulting oil was distilled through a short column to give 6.3 g (b.p. 120° -125° C. at 0.1 mm of Hg) of 4,4-dimethyl-1,2-dihydro-4H-3,1-benzoxazine, as a colorless oil. Elemental analysis showed: %C, calc. 73.6, found 68.3: %H, calc. 8.0, found 7.6; %N, calc. 8.6, found 8.6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: COc1nnc(Cl)cc1I
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nnc(Cl)cc1Nc1ccncn1
Temperature: 100 °C

Procedure:
In a dried pressure flask was placed compound 2 (1.0 g, 3.70 mmol), 4-aminopyrimidine (352 mg, 3.7 mmol), sodium phenoxide (860 mg, 7.4 mmol), Pd2(dba)3 (170 mg, 5 mol %), and Xantphos (150 mg, 7 mol %). The flask was evacuated and filled with N2 3× and then 20 mL anhydrous dioxane was added, The mixture was heated at 100° C. for 12 hours. The cooled mixture was diluted with ethyl acetate and water, filtered, separated, the ethyl acetate layer extracted 1× with ethyl acetate, the combined ethyl acetate layers washed with brine 4×, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (silica) CH2Cl2/MeOH to give 3.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C(O)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:27]([C:28](=[O:29])[NH:30][CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=4[F:36])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCOC(=O)N1CCCOc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Yield: 51.6 %

Procedure:
2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (102 mg, 0.433 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (150 mg, 0.476 mmol) were placed in isopropyl alcohol (3.00 mL, 39.2 mmol) and 10-camphorsulfonic acid (10.0 mg, 0.0433 mmol) was added. The reaction was microwaved on 300 watts, 120° C. for 20 minutes and then concentrated under reduced pressure. The residue was taken up in DCM (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester as a yellow foam (115 mg, 52%). LCMS (m/e) 515 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.37 (bs, 1H), 8.56-8.47 (m, 1H), 8.17 (s, 1H), 7.52-7.36 (m, 4H), 7.28-7.17 (m, 1H), 6.79 (d, 1H, J=8.7 Hz), 4.20-3.81 (m, 4H), 3.70-2.42 (m, 1H), 2.73 (d, 3H, J=4.5 Hz), 1.95-1.80 (m, 2H), 1.36-0.98 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[C:15](=[S:30])(OC1C=CC=CN=1)OC1C=CC=CN=1>ClCCl>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:7]([CH2:6][CH:5]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]=[C:15]=[S:30])[CH3:2]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CCOC1=CCc2cccc(N)c2C1
Solvent: ClCCl
Product: CCOC1=CCc2cccc(N=C=S)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product of Example 1E (200 mg, 1.06 mmol) in dichloromethane (2.5 mL) was added to a solution of O,O-dipyridin-2-yl thiocarbonate (246 mg, 1.06 mmol) in dichloromethane (5 mL) at room temperature. After stirring at room temperature for 18 hours, the mixture was concentrated, then filtered through silica gel and eluted with 5% ethyl acetate-hexane. Evaporation of the filtrate in vacuo afforded the title compound as a pale pink solid, 225 mg (92%). 1H NMR (DMSO-d6) δ 7.21-7.27 (m, 3H), 4.86 (t, 1H, J=3.6 Hz), 3.81 (q, 2H, J=7.0 Hz), 3.49 (q, 2H, 4.4 Hz), 3.35 (t, 2H, J=5.2 Hz), 1.27 (t, 3H, J=7.0 Hz); MS (DCI+) m/z 232 (M+H).