Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([OH:44])[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([O:44][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.32 g of tert-butyldiphenylsilyl chloride and 2.32 g of imidazole were added in order to a dimethylformamide (60 ml) solution of 3.61 g of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl[CH2:17][C:18]1[S:19][C:20]([CH:23]2[CH2:25][CH2:24]2)=[N:21][N:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]1[S:19][C:20]([CH:23]2[CH2:25][CH2:24]2)=[N:21][N:22]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: ClCc1nnc(C2CC2)s1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(C3CC3)s2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 2-(chloromethyl)-5-cyclopropyl-1,3,4-thiadiazole: MS (ESI) m/z 365 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:24][C:25]1([C:28]2[CH:29]=[C:30]([NH:40][C:41]([NH:43][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]([O:54][CH:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)=[N:46][CH:45]=3)=[O:42])[N:31]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:32]=2)[CH2:27][CH2:26]1.[CH3:61][C:62]1([C:65](O)=[O:66])[CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:61][C:62]1([C:65]([N:58]2[CH2:59][CH2:60][CH:55]([O:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:44]([NH:43][C:41]([NH:40][C:30]4[N:31]([C:33]5[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=5)[N:32]=[C:28]([C:25]5([CH3:24])[CH2:27][CH2:26]5)[CH:29]=4)=[O:42])=[CH:45][N:46]=3)[CH2:56][CH2:57]2)=[O:66])[CH2:64][CH2:63]1
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place EDCI (0.147 g, 0.77 mmol), HOBt (0.10 g, 0.77 mmol), 1-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[1-(piperidin-4-yloxy)-isoquinolin-4-yl]-urea dihydrochloride (Preparation 3, 0.16 g, 0.64 mmol) and 1-methyl-1-cyclopropyl carboxylic acid (1.1 eq) in a flask under N2. Add dichloromethane (5 mL) follow by DIPEA (0.22 mL, 1.28 mmol) and stir at room temperature overnight. Evaporate solvent to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 50-100% to give 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a free base. ES+ (m/z) 579.3 (M+H).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15.75 h
Yield: 97.2 %

Procedure:
Ethyl difluoroacetate (3.51 g, 28.3 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.12 g, 28.3 mmol) followed by 2-acetyl-5-chlorothiophene (4.12 g, 25.6 mmol). A pink precipitate formed after 5 minutes which was dissolved by adding ether (10 mL) and THF (10 mL) to the reaction. The reaction was stirred at room temperature overnight (15.75 hours), then treated with 3N HCl (15 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a red solid (5.94 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (2.02 g, mp 72°-77° C., 33%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H) , 7.57 (d, J=4.2 Hz, 1H) , 7.01 (d, J=4.2 Hz, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.01 (d); M+238.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21]CC[CH2:18]1>O>[CH3:18][C:17]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)([CH3:21])[C:22]#[N:23]
Reactant: C1CCNCC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCCCC1
Yield: 77 %

Procedure:
The title compound (2.33 g, 77%) was prepared from piperidine hydrochloride (2.43 g, 20 mmol), acetone (1.16 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.46 (2H, m), 1.50 (6H, s), 1.63 (4H, m), 2.59 (4H, m).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:26]3[CH2:27][C:28]4[CH2:29][NH:30][CH2:31][C:24]=4[CH2:25]3)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1NCC2=C1CNC2
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4=C(CNC4)C3)c(F)c21
Yield: 91.3 %

Procedure:
1-tert-Butyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.32 g), 3,7-diazabicyclo-[3.3.0] oct-1(5)-ene dihydrobromide (0.3 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.55 ml) in acetonitrile (12 ml) was refluxed for 5 hours. The produced precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.38 g, yield 92%)
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[CH2:21]([O:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[C:17]([Br:19])[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
To an ice-cold solution of 1-benzoyl-3-(3-benzyloxy-5-bromo-phenyl)thiourea (33.0 g, 74.70 mmol) in THF (500.0 mL) was added a solution of NaOH (15.0 g, 375.0 mmol) in H2O (180.0 mL). The resulting reaction mixture was stirred at 65° C. for 15 h. The reaction mass was then cooled to room temperature, added water and extracted with EtOAc (3×1.0 L). The combined organics was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the desired compound (23.50 g, 94%) that was carried forward to the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[C:20]([F:26])[CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][C:20]=3[F:26])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(Cl)cc1F
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3F)c21
Yield: 63.8 %

Procedure:
The title compound (cis/trans=24:76) was prepared as a white powder in 63.8% yield in a similar procedure to that described in Example 1 by using using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 4-chloro-2-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)[CH:3]=1.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[F:32])[CH3:19].CS(Cl)(=O)=O>N1C=CC=CC=1.CCOC(C)=O>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([S:28](=[O:29])(=[O:30])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[N:10]2)=[CH:24][C:23]=1[F:32])[CH3:19]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Reactant: Nc1ccc(Cl)cc1-n1nnc2ncccc21
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (153.5 mg, 0.626 mmol) in pyridine (2 mL) was added 4-chlorosulfonyl-2-fluoro-benzoic acid ethyl ester (200 mg, 0.752 mmol) followed by methanesulfonyl chloride (32 μL, 0.47 mmol) at 0° C. under a nitrogen atmosphere. The resultant reaction mixture was allowed to warm to room temperature and stirred for overnight. The following day, reaction mixture was diluted with EtOAc (25 mL), washed with 2N HCl (2×15 mL), dried (Na2SO4) and evaporated. The resulting bis-sulfonamides crude mixture was treated with 1 N TBAF (in THF, 2 mL) at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc (25 mL), washed with 2 N HCl (2×15 mL), water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated. The resulting crude product was purified by SiO2 chromatography using 50→100% EtOAc in hexanes solvent system to obtain 4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-2-fluoro-benzoic acid ethyl ester. Step 2: The title compound was prepared via conversion from its ethyl ester according to general procedure Y: MS (ES) M+Na expected 484.0, found 484.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-5-methoxy-N-methyl-benzamide as a lyophylate (22%); 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.39 (s, 1H), 8.77 (bs, 1H), 8.55 (bs, 1H) 8.17 (s, 1H), 7.63 (d, J=8.17 Hz, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.03 (d, J=8.89 Hz, 1H), 6.87 (d, J=8.68 Hz, 1H), 3.82 (s, 3H), 2.80 (d, J=3.80 Hz, 3H), 2.50 (m, 2H), 2.16 (m, 2H), 1.27 (s, 6H); MS (m/e) 495.45 (M+H).
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N:25]=[C:26]=[S:27])=[C:18]([F:28])[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([NH:25][C:26]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]2)=[S:27])=[C:18]([F:28])[CH:17]=1
Reactant: C1CCNNC1
Reactant: O=[N+]([O-])c1cc(N=C=S)c(F)cc1Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred, cold (-5° C.) solution of 8.56 g (0.0400 mole) of perhydropyridazine hydroiodide in 150 mL of methylene chloride was added dropwise 12.2 g (0.120 mole) of triethylamine. This mixture was stirred for approximately 30 minutes. A solution of 8.0 g (0.034 mole) of 4-chloro-2-fluoro-5-nitrophenylisothiocyanate in methylene chloride was added dropwise to the reaction mixture while maintaining a reaction temperature of -20° C. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for two days. The solvent was removed from the mixture by evaporation under reduced pressure leaving a residue. The residue was subjected to column chromatography on silica gel, eluting with ethyl acetate:n-heptane (50:50), to yield 10.4 g of N-[(4-chloro-2-fluoro-5-nitrophenyl)aminothiocarbonyl]perhydropyridazine as a solid, mp 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.[CH2:26](Br)[CH:27]=[CH2:28].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:28]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCn1nc([N+](=O)[O-])c(NCc2ccc(OC)c(OCCC)c2)c(Cl)c1=O
Reaction time: 1.5 h

Procedure:
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 820 mg of allyl bromide, 937 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue thereby obtained, the mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography by using a solvent mixture of benzene: ethyl acetate (85:15 v/v) as the eluent, to obtain 394 mg of the above identified compound having a melting point of from 62.5° to 64° C. as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([NH:11]C(=O)OCC2C=CC=CC=2)[CH3:10])=[O:7])=[CH:4][CH:3]=1.[ClH:24].[H][H]>CO.[Pd]>[ClH:24].[NH2:11][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)NC(C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)NC(C)N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of Example 29B (66 mg, 0.21 mmol) in methanol (9 mL) at ambient temperature was treated with 10% Pd/C (20 mg) aid sufficient 1M HCl to solubilize the substrate (ca. 0.20 mL). The system was equipped with a hydrogen balloon and stirred for 4 hours at ambient temperature. The reaction mixture was purged with nitrogen, filtered through diatomaceous earth (Celite®), rinsed with methanol and water, and the aqueous filtrate was washed with diethyl ether (2×15 mL). The aqueous layer was lyophilized providing 38 mg of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:13]
Reactant: NC(N)=O
Reactant: Brc1cccc(Br)n1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 5 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
2,6-dibromo pyridine (79 g, 334 mmol) was dissolved in 800 ml of dry dichloromethane and cooled under nitrogen to 5° C. then urea hydrogen peroxide (104 g, 1.1 mol) was added in one portion. When the mixture had cooled again to 3° C., a solution of trifluoro acetic acid anhydride (140 mL, 1 mol) in 100 ml DCM was added via dropping funnel over 45 min, whilst keeping the temperature between 5-7° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was cooled in an ice bath to 10° C. and 10% aq. Na2SO3 (˜50 g/500 ml) was added dropwise over 60 minutes until test with starch iodide paper was negative. The resulting mixture was filtered to remove a quantity of fluffy solid and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 ml) and the combined extracts were dried over MgSO4 and concentrated under reduced pressure to give a light brown solid. Recrystallisation of crude product using 600ml of boiling acetone gave 48.47 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[S:11]2)=[C:5]([CH3:19])[CH:4]=1)#[N:2].[CH2:20](Br)[CH:21]([CH3:23])[CH3:22]>>[CH2:20]([N:14]1[CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[S:11][C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:19])[CH:21]([CH3:23])[CH3:22]
Reactant: Cc1cc(C#N)ccc1N=C1NCC2(CCCC2)S1
Reactant: CC(C)CBr
Product: Cc1cc(C#N)ccc1N=C1SC2(CCCC2)CN1CC(C)C

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1a to give 2-(4-cyano-2-methylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-2-methylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].ClCCCl.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:20]=[C:21]([CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:23][CH:24]=1>O>[F:17][C:18]([F:29])([F:30])[C:19]1[CH:20]=[C:21]([CH2:25][C:26]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Cc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anisole (32.4 g) and aluminium trichloride (36.0 g) are added to 1,2-dichloroethane (240 ml). The mixture is cooled to -5° and (3-trifluoromethylphenyl)-acetyl chloride (66.8 g) is slowly added. The mixture is stirred for 11/2 hours and poured into a mixture of crushed ice (400 g) and water (150 ml). After heating to room temperature, the compound is extracted with ether (3×200 ml). The combined organic phases are washed with a 2% aqueous solution of sodium hydroxide (200 ml and with water (3×200 ml), dried over magnesium sulphate and the solvents are removed invacuo. The residue is recrystallised from hexane. The product is dried in vacuo to constant weight to yield 2-(3-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethanone, m.p. 94°-95°.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:26]3[CH2:27][CH2:28][C:23]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:24][CH2:25]3)=[CH:4][C:5]=2[N:6]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.00 g, 2.87 mmol) in DMF (20 mL) were added 1,4-dioxa-8-aza-spiro[4.5]decane (1.06 mL, 8.62 mmol) and cesium carbonate (1.8 g, 5.75 mmol). The resulting mixture was stirred at RT for 90 min. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as an orange solid (0.97 g, 82%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1.F[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[CH3:3][C:4]1[N:5]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1c[nH]c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2C#N)c(C)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium hydride (8.65 grams 60%, 0.216 mol) was stirred in 75 mL of anhydrous dimethylformamide. To this was added dropwise a solution of 2,4-dimethylimidazole (20.75 grams, 0.216 mol) in 100 mL of DMF. After stirring at ambient temperature for 1 hour a solution of 2-fluorobenzonitrile (23.0 mL, 0.216 mol) in 75 mL of DMF was added dropwise. This was stirred at 50° C. for 2 hours and then at ambient temperature for 16 hours. The mixture was then poured into water and the product extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The crude product was chromatographed (silica gel) and eluted with 19:1 dichloromethane-methanol then 9:1 dichloromethane-methanol to afford the product as a solid. LCMS data confirmed structure.
Reaction SMILES: Cl.ClC1C=C([C@@:9]2([OH:18])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[NH:11][C@@H:10]2[CH3:17])C=CC=1.C(OCC)C.[OH-].[Na+]>O>[CH3:17][CH:10]1[CH:9]([OH:18])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[NH:11]1
Reactant: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1NC(C)(C)COC1O
Reaction time: 0.5 h

Procedure:
(+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride may be converted back to its free base by the following process. A 3.0 g sample of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride was dissolved in water (100 mL) and diethyl ether was added (200 mL). The mixture was chilled in an ice bath and the pH was adjusted to >10 with 1.0N aqueous sodium hydroxide. After stirring for 30 min., the phases were separated and the aqueous phase was extracted with diethyl ether. The combined diethyl ether extracts were dried (Na2SO4) and concentrated in vacuo to give 2.6 g of (+/−)-(2R*,3R*)-2-(3-chlophenyl)-3,5,5-trimethyl-2-morpholinol as a white solid. This was used without further purification for the chiral chromatography described below.