Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20])=[O:7])[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane (50 ml) was added to a stirred solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine (0.02 g, 0.164 mmol) and triethylamine (3.34 g, 33.0 mmol) in dichloromethane (50 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for a further 2 hours. The solvent was evaporated under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane and methanol (250 ml), and then the solution washed with 1N hydrochloric acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude material was chromatographed on silica gel (200 g), eluting with a 97:3 mixture of dichloromethane and methanol, to give a pink solid; crystallisation from ethyl acetate-hexane gave the pyrazole-5-carboxamide as a pale pink solid (2.2 g, 40%), m.p. 153-155° C. Found: C,61.66; H,6.77; N,16.95. C17H22N4O3 requires C,61.80; H,6.71; N,16.96%.
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([CH:19]=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CS(C)=O>[CH2:33]([O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][C:20]3([CH:19]([C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH2:6]3)[CH2:21][CH2:22]2)=[CH:36][CH:35]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2CCC3(CC2)CC3C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 7.6 %

Procedure:
5.11 g of trimethylsulfonium iodide (23.23 mmol, 4 eq.) are dissolved with stirring in 20 mL of DMSO in a 250 mL three-necked flask under a nitrogen atmosphere. 2.61 g of potassium tert-butoxide (23.23 mmol, 4 eq.) are added and the reaction medium is stirred for 3 hours. 2 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate dissolved in 5 mL of DMSO are added and stirring is continued for 2 days. 2.56 g of trimethylsulfonium iodide (11.61 mmol, 2 eq.) are dissolved in 20 mL of DMSO in a 25 mL three-necked flask under a nitrogen atmosphere, and 1.0 g of potassium tert-butoxide (11.61 mmol, 2 eq.) is added with stirring. After 3 hours, this reaction medium is added to the 250 mL three-necked flask and stirring is continued for 18 hours. Ethyl acetate is added. The organic phase is washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and filtered. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 0.159 g of tert-butyl 6-(4-ethoxycarbonylphenyl)spiro[2.5]octane-1-carboxylate is obtained.
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[OH:17][C@@H:18]1[CH2:23][C@H:22]([C:24]#[N:25])[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19]1.[CH3:28][C:29]1[C:37](O)=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[N:32][NH:33]2>C1(C)C=CC=CC=1>[CH3:26][C:21]1([CH3:27])[CH2:20][CH2:19][C@@H:18]([O:17][C:37]2[C:29]([CH3:28])=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)[CH2:23][C@@H:22]1[C:24]#[N:25]
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: CC1(C)CC[C@H](O)C[C@@H]1C#N
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](C#N)C2)ccc2[nH]ncc12
Reaction time: 4 h
Yield: 36.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 90%-cyanomethylenetri-n-butylphosphorane (1.05 g, 4.05 mmol) in toluene (5 ml) was added dropwise to a solution of cis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile (500 mg, 3.37 mmol) in toluene (12 ml) at room temperature, followed by adding thereto the 4-methyl-1H-indazol-5-ol (507 mg, 3.54 mmol) obtained in Example 402, and the resulting mixture was heated to 100° C. After 4 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. The aqueous layer was re-extracted with chloroform and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanecarbonitrile (351.1 mg, 46%).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[C:24]([O:28][C:29](=[O:47])[C@@H:30]([NH2:46])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:47])[CH:30]([NH:46][C:5](=[O:7])[CH:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: CC(C)CC(NC(=O)N1CCN(c2ccccc2)CC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 46 %

Procedure:
A solution of the product from Example AG ((2S)-4-methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]-pentanoic acid) (0.93 g, 2.9 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.0 g, 2.9 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white crystals (0.84 g, 46%), mp=67-69° C.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1O

Procedure:
A mixture of vanillin (30.4 g, 0.2 mol), rhodanine (26.6 g, 0.2 mol), anhydrous sodium acetate (41 g, 0.5 mol) and glacial acetic acid was stirred and heated at reflux for one and one-half hours. The cooled reaction mixture was added to water (1200 mL) and the yellow-orange solid that separated was collected, washed with water and air dried; yield 46 g.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:22][C:23]([CH3:24])=[O:25])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc2c(C)cc(=O)oc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc2oc(=O)cc(C)c2cc1C

Procedure:
A mixture of 4,6-dimethyl-7-hydroxycoumarin (III) (5.0 g), anhydrous K2CO3 (10 g), chloroacetone (2.5 ml) and acetone (150 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 4,6-dimethyl-7-acetonyloxycoumarin (XXXVII) (5.1 g; m.p. 190° C.) ##STR42##
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[CH:2].[CH2:18]([N:25]=[N+:26]=[N-:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(C)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:18]([N:25]1[CH:2]=[C:1]([C:3]2[N:4]=[C:5]3[C:11]([C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:10][NH:9][C:6]3=[N:7][CH:8]=2)[N:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cn(Cc4ccccc4)nn3)nc12
Yield: 22.7 %

Procedure:
A solution of 1-(2-ethynyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.100 g, 0.44 mmol), benzyl azide (0.055 mL, 0.44 mmol), CuSO4 (0.007 g, 0.04 mmol), and L-ascorbic acid (0.078 g, 0.44 mmol) in 3 mL of tert-butanol and 3 mL of water was stirred for 1.5 h, then diluted with 30 mL of water and extracted with 100 mL of ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->50% EtOAc/hexanes) afforded 0.036 g (23%) of 1-[2-(1-benzyl-1H-[1,2,3]triazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as an off-white solid. MS: 361 M+1, M.P. 235.0-237.0° C.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([CH2:32][CH2:33][NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([CH2:32][CH2:33][NH:34][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Reactant: NCCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2c3nc(C)nc(NCCCc4ccccc4)c3n3ccccc23)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (15 mg) and N-benzylethylamine (0.04 mL) in DMSO (0.4 mL) is heated to 110° C. for 2 hours. The mixture is allowed to cool, diluted with aqueous ammonium chloride, and extracted twice with 50% ethyl ether in hexane. The combined extracts are washed with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (10% to 20% ethyl acetate in hexane) gives 22 mg of the title compound (compound 5, Table 1) as a yellow oil: 1H nmr (400 MHz, CDCl3) d 1.17 (t, 3 H), 2.00 (s, 6 H), 2.38 (s, 3 H), 2.70 (s, 3 H), 3.40 (q, 2 H), 4.72 (s, 2 H), 6.68 (t, 1 H), 7.00 (s, 2 H), 7.03 (d, 1 H), 7.13 (d, 1 H), 7.29 (d, 1 H), 7.35 (t, 2 H), 7.41 (d, 2 H), 8.61 (d, 1 H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:22](C)=O.[Na+]>C(Cl)Cl.CO>[CH3:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: c1nc(-c2ccsc2)nc(N2CCNCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ncnc(-c3ccsc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-piperazin-1-yl-4-thiophen-3-yl-[1,3,5]triazine (0.17 mmol) in CH2Cl2/MeOH (3:1, 4 mL) was added formaldehyde (37 wt. % in water, 22 mg, 0.26 mmol). After stirring for 1 h at room temperature, NaB(OAc)3H (72.8 mg, 0.34 mmol) was added. The reaction mixture was stirred overnight at room temperature, then quenched with 1 N NaOH (3 mL), and extracted with EtOAc (50 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried, and concentrated to yield a light yellow oil.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41]N(C)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1
Reactant: NCCc1ccncc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccncc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-pyridin-4-yl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C20H21FN3O3: 370.1567. found: 370.1568. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s, 3), 3.23 (t, 2, J=7), 3.90 (t, 2, J=7), 4.20 (s, 2), 4.60 (s, 2), 7.03 (m, 2), 7.21 (m, 2), 7.80 (d, 2, J=6), 8.73 (d, 2, J=6). 13C NMR (125 MHz, CDCl3) δ: 34.55, 34.63, 42.47, 49.04, 51.55, 109.53, 114.58, 115.74, 115.91, 127.10, 129.30, 129.50, 131.76, 141.92, 153.22, 158.36, 160.92, 161.23, 161.43, 163.40, 165.33, 166.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]Br.O>CC(O)=O>[Br:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: COc1cc(CC(=O)O)ccc1F
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetic acid (5.0 g, 27.1 mmol) in AcOH (20 ml) was added bromine (1.5 ml, 29.8 mmol). The mixture was stirred at room temperature for three hours. Water was added and the precipitate was isolated by filtration. The white solid was washed with water and dried to give (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.21 g, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].[Si:10]([O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[NH:34][C:35](=[O:44])[C:36]2[CH:41]=[C:40](I)[CH:39]=[CH:38][C:37]=2[F:43])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:40]2[CH:39]=[CH:38][C:37]([F:43])=[C:36]([CH:41]=2)[C:35]([NH:34][C:25]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:24]=2[N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH2:19]2)=[O:44])=[CH:4][N:5]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Temperature: 70 °C

Procedure:
In a 16×120 mm resealable pyrex tube, 5-ethynylpyrimidin-2-amine (0.080 g, 0.67 mmol), (R)—N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide (0.210 g, 0.34 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.017 mmol), and Copper(I) iodide (0.0032 g, 0.017 mmol) were taken up in CH3CN and Triethylamine (0.71 ml, 5.1 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70° C. overnight. The reaction was cooled, and transferred to a 50 mL RBF with EtOAc. The mixture was concentrated in vacuo, and the resulting solid was treated with 10% MeOH in CH2Cl2 and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide as an off-white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>C1COCC1.CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-methoxyphenyl)-quinoline (210.7 mg, 615 mmol) in THF 5 mL and MeOH 12 mL was added palladium, 10 wt. % on activated carbon (0.329 mmol) and placed under a medium balloon containing H2. The reaction was complete after 2 h, it was filtered (Celite™) and solvents removed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:20][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(Br)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Brc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Bromobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 5.4 %

Procedure:
A mixture of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3, 2-(6-benzyl-pyridin-3-yl)-acetohydroximoyl chloride (88 mg, 0.34 mmol) described in Manufacturing Example 210-1-7, triethylamine (77 mg, 0.76 mmol), and tetrahydrofuran (5 mL) was stirred for 25 minutes at 50° C. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1, ethyl acetate) to obtain the title compound (4.6 mg, 5.3%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC3C=CC=CC=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[C:3]1=[O:26]>[Pd].C1COCC1.CO>[OH:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:26])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of methyl 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate (Intermediate 9) (1.42 g, 4.0 mmol) was added to a suspension of 10% palladium on carbon (140 mg, catalytic) in THF (40 mL) and methanol (40 mL). The mixture was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give the product (1.06 g, 100%). 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.56-2.68 (m, 1H), 2.97 (s, 3H), 3.37-3.55 (m, 2H), 3.86 (s, 3H), 4.93 (t, 1H), 6.81 (s, 1H), 7.04 (s, 1H), 7.12 (s, 1H), 7.66 (s, 1H); m/z 266 (M+H)+
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:15]1[C:16]([O:20][CH3:21])=[CH:17][C:18]([NH2:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1ccc(Cl)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (commercially available, for example, from Aldrich) (9.1 g, 32 mmol) was added over 20 minutes to a stirred solution of 6-chloro-3-methoxyaniline (commercially available, for example, from Apollo Scientific) (10.0 g, 63 mmol) in ethyl acetate (150 ml) at −5° C. The resulting solution was stirred at −5° C. for 1 hour then washed with a solution of potassium carbonate (6 g, 43 mmol) in water (40 ml and then with water (20 ml). The resulting solution was concentrated under reduced pressure to give 4-bromo-2-chloro-5-methoxyaniline as a pale brown solid (14.3 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([Cl:20])=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a suspension of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid (0.66 g, 2.58 mmol) and oxalyl chloride (0.9 mL, 10.32 mmol) in dichloromethane (30 mL) was added 2 drops of N,N-dimethylformamide. After the mixture was stirred 16 hours at room temperature, the volatiles were removed in vacuo to obtain 4-chloro-5-(4-chlorophenyl)isoxazole-3-carbonyl chloride (0.71 g, 2.53 mmol).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.O>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Potassium tert-butoxide (2.03 g, 21.1 mmol) in tetrahydrofuran (20 mL) was mixed with diethyl cyanomethylphosphonate (3.54 g, 20.0 mmol) in tetrahydrofuran (20 mL) under cooling with ice and stirred for 30 minutes. The reaction mixture was mixed with tert-butyl 3-oxoazetidine-1-carboxylate (2.96 g, 17.3 mmol) obtained in Reference Synthetic Examplea 112 in-tetrahydrofuran (20 mL) under cooling with ice and then stirred at room temperature for 1 day. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v)) to give the title compound as a colorless solid (1.93 g, yield 58%).