Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([O:15]C)=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>>[C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([OH:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(C)(C)C)[nH]c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1cc(C(=O)O)c([N+](=O)[O-])[nH]1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To methyl 5-tert-butyl-2-nitro-1H-pyrrole-3-carboxylate (900 mg, 3.98 mmol) was added 12% aqueous KOH (5 mL), and the resulting reaction mixture was stirred at 80° C. for 30 min. The reaction mixture was poured into 1N aqueous HCl (excess), the aqueous phase was extracted 3 times with dichloromethane, the combined organic layers was dried and concentrated under vacuum to afford 5-tert-butyl-2-nitro-1H-pyrrole-3-carboxylic acid (5) as yellow solid (750 mg, 89%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:9][NH:10][C:11](=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:14]1>N1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:15]2[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:23])([F:24])[F:22])[C:17](=[O:18])[N:13]([CH2:12][C:11]([NH:10][CH2:9][CH:8]([NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:42])[F:43])=[O:33])[N:14]=2)=[CH:27][CH:28]=1
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 13 μl of methanesulphonyl chloride were added to a solution of 90 mg (0.15 mmol) of the compound of Example 56A in 1.5 ml of pyridine. The mixture was stirred at RT for 1 h, and another 12 ml of methanesulphonyl chloride were added (0.32 mmol, 2.1 eq. in total). After 1 h, the volatile components were removed on a rotary evaporator. The residue was dissolved in a little DMSO and purified by preparative HPLC [Method 8]. This gave 59 mg (61% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]1)=[O:15].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:18]1)=[O:15])#[N:1]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(N)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC#N)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(3-amino-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (233 mg) was dissolved in pyridine (5 ml), trifluoroacetic anhydride (116 μl) was added at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate. 1M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give the object product (197 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([C:19]([CH3:22])=[CH:20][CH:21]=1)[C:17]#[N:18].[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[F:13][C:14]1[C:15]([Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:16]([C:19]([CH3:22])=[CH:20][CH:21]=1)[C:17]#[N:18]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(F)cc1C#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)c([Si](C)(C)C)c1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
n-Butyllithium (1.40M in hexanes, 11.8 mmol, 8.44 ml) was added dropwise to a stirred solution of diisopropylamine (1.84 ml) in THF (5 ml) at 0° C. After 30 min., the solution was cooled to -78° C. and 3-fluoro-6-methylbenzonitrile (1.60 g, 11.8 mmol) in THF (5 ml) was added dropwise. The pale purple anion was stirred for 20 min., trimethylsilylchoride (3.0 ml, 24 mmol) was added and the mixture warmed to room temperature over 1 h, evaporated, the residue taken up in a small amount of diethyl ether and filtered. Evaporation of the filtrate gave an off-white crystalline solid (2.3 g), m.p. 71-73° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26].C([O-])=O.[NH4+]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:22])([CH3:23])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(Cl)n2)s1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (75 mg, 0.147 mmol) and ammonium formate (93 mg, 1.47 mmol), the title compound was obtained as a yellow solid (23 mg, 34% yield). MS (ESI): 475 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[OH-].[Na+]>O1CCCC1.B.O1CCCC1.[Cl-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromoisonicotinic acid (678 mg) in tetrahydrofuran (30 ml), 8.4 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred overnight at room temperature. To the reaction solution was added 7.9 ml of 1N aqueous sodium hydroxide, and the mixture was stirred for 2 hours. The reaction solution was diluted with a saturated aqueous sodium chloride solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: chloroform/(chloroform/methanol (9:1)) (100:0-0:100)) to afford the title compound as a white crystal.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:23])[N:5]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([Cl:21])=[CH:13][C:12]=2[F:22])[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].S(OC)(O[CH3:28])(=O)=O>>[CH2:1]([C:3]1[C:4](=[O:23])[N:5]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:19])[CH3:20])[C:14]([Cl:21])=[CH:13][C:12]=2[F:22])[C:6](=[O:10])[N:7]([CH3:28])[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(C)[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Reactant: COS(=O)(=O)OC
Product: CCc1c(C)n(C)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 124°-125° C.;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18]3[CH:24]=[CH:25][S:26][C:17]=23)=[CH:11][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18]3[CH:24]=[CH:25][S:26][C:17]=23)=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCNc2c(C#N)cnc3ccsc23)s1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc2ccsc2c1NCCc1cnc(N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A mixture of {5-[2-(6-cyano-thieno[3,2-b]pyridin-7-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (36.1 mg, 0.09 mmol) and trifluoroacetic acid (1 ml) in 4 ml of dichloromethane was stirred at room temperature for 16 hr. Dichloromethane was evaporated, and the residue obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over MgSO4, filtered, and concentrated in vacuum to give a yellow crude product 24 mg. (89%). 1H NMR (300 MHz, CD3OD) δ 8.85 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.7 Hz, 1H), 7.14 (s, 1H), 4.19 (t, J=7.2 Hz, 2H), 3.22 (t, J=7.2 Hz, 2H); LC-MS (ESI) m/z 302.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[F:12][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([CH:28]=[O:29])=[CH:15][CH:14]=2)[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(Br)cc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate (Preparation 5, 1.0 g, 3 mmol) in THF (10 mL) at −78° C. was slowly added n-BuLi (2.1 mL of 1.6M solution in hexanes). The reaction was stirred at −78° C. for 15 minutes at which time DMF (0.5 mL, 6 mmol) was added. Reaction mixture was allowed to warm to room temperature and stir for additional 1 hour. Saturated aqueous NH4Cl (10 mL) was added and the aqueous phase was extracted with ether (2×10 mL). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. Crude product was chromatographed on silica (12 g column) using a gradient of 0-30% EtOAc/hexanes in a 12 minute run. Yield 460 mg. LC/MS retention time=3.004 minutes; MS calculated for (C15H18FNO3), 279.127; found 180.2 M-BOC. 1H NMR (CDCl3) δ 10.0 (s, 1H), 8.0 (d, 2H), 7.7 (d, 2H), 4.5 (m, 2H), 4.2 (m, 2H), 1.6 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 148.2 %

Procedure:
4-t-Butylphenol (2.76 g, 18.4 mmol) was dissolved in dichloromethane (25 ml). Sulfuryl chloride (1.6 ml, 9.9 mmol) was added dropwise to the obtained solution, and they were stirred at room temperature for 3 days and then concentrated under reduced pressure. After the purification by the silica gel column chromatography, 2-chloro-4-t-butylphenol (yield: 2.71 g, 80%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])[SH:3](=[O:5])=[O:4]>C(O)(=O)C.[Pt]=O>[CH3:1][N:2]([CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])[SH:3](=[O:4])=[O:5]
Reactant: CN(CCc1cc([N+](=O)[O-])c(F)cc1Cl)[SH](=O)=O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CN(CCc1cc(N)c(F)cc1Cl)[SH](=O)=O
Yield: 82.7 %

Procedure:
By the method of Example 3, Step C, 1.0 g (0.0034 mole) of N-methyl-N-(2-chloro-4-fluoro-5-nitrobenzyl)methylsulfonamide was hydrogenated in the presence of 0.3 g of platinum oxide in 90 ml of glacial acetic acid, yielding 0.75 g of N-methyl-N-(2-chloro-4-fluoro-5aminobenzyl)methylsulfonamide as a yellow-tan solid, m.p. 108°-109° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH:4]1[CH3:35].[CH2:37]([O:39][C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:41])[C:42]1[CH:49]=[CH:48][C:45](/[CH:46]=[C:12](/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:3]([CH3:36])([CH3:2])[CH:4]([CH3:35])[C:5]3([CH3:33])[CH3:34])\[CH3:13])=[CH:44][CH:43]=1)[CH3:38]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: CC1C(C)(C)c2ccc(C(C)[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2C1(C)C
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)C(C)C3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(1,1,2,3,3-pentamethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(1,1,2,3,3,-pentamethyl-5-indanyl)propenyl]-benzoic acid ethyl ester of melting point 79°-80° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH3:2].[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:12]2[CH2:13][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:15]2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCOCC1CCC(=O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOCC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-(ethoxymethyl)cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Cl:17][C:18](OC(Cl)(Cl)Cl)=[O:19]>O1CCCC1>[Cl:17][C:18]([O:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
To a solution of benzyl (2S)-2-hydroxy-4-methylvalerate (1.00 g) in tetrahydrofuran (20 ml) was added trichloromethyl chloroformate (0.55 ml) at room temperature. The solution was refluxed for 11 hours and the solvent was removed by evaporation at atmospheric pressure to give benzyl (2S)-2-chlorocarbonyloxy-4-methylvalerate (1.26 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[CH3:30][NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:31][CH3:30])=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: CN
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (40 mg, 0.1 mmol) was reacted with methylamine (2M, 0.2 mL) in THF to provide 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 139. LC/MS (ESI+): m/z 422 (M+H). 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.5, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=10.9, 1H), 7.68-7.51 (m, 4H), 7.47-7.28 (m, 2H), 4.50 (t, J=15.6, 4H), 2.76 (d, J=4.5, 3H)
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:31]1([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2C(F)(F)F)=[O:38])CCNCC1>CN(C=O)C.O>[C:37]([NH2:31])(=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (397 mg, 3.08 mmol) was added drop wise to 4-(hydroxybenzoyl amino)-acetic acid (200 mg, 1.03 mmol) in DMF (6 mL). EDCI (294 mg, 1.54 mmol) and HOBT (166 mg, 1.23 mmol) were added consecutively and, after 15 mins, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone (390 mg, 1.33 mmoles) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded 4-hydroxy-N-[2-Oxo-2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl]-benzamide in 65% yield. LC-MS purity: 93%, 1H NMR (DMSO-D6): δ 10 (s, 1H), 8.3 (d, 1H), 7.8 (m, 5H), 7.5 (t, 1H), 6.8 (d, 2H), 4.1 (d, 2H), 3.6 (m, 5H), 3.1 (m, 3H).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:36]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH3:36])[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1
Reactant: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(C)C2(CC2)C1
Reaction time: 12 h

Procedure:
A solution of N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8 (0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide D9. 1H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.98 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.78 (m, 2H), 2.51 (m, 4H), 2.31 (s, 3H), 2.10 (s, 3H), 0.62 (m, 2H), 0.50 (m, 2H). MS (m/z) (M+1)+: 537.1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:20]Br.O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])([Br:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2F)CC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Br)(C(=O)c2cc(F)ccc2F)CC1
Reaction time: 0.21 h

Procedure:
To a stirred solution of 11.2 g of 1-acetyl-4-(2,5-difluorobenzoyl)piperidine in 225 ml of glacial acetic acid was added dropwise over 0.5 hr a solution of 13.5 ml (42.1 g) of bromine in 115 ml of glacial acetic acid at a rate such that the temperature remained between 10°-12° C. The mixture was stirred for an additional 10-15 mins, poured into water, extracted twice with ethyl acetate, and the solvent evaporated to provide an oil. The oil was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to provide product as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:13][CH3:14].CCN(CC)CC.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:14])[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: CNCc1c(C)c2ccccc2n1C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c(C)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred solution of 1,3-dimethyl-2-(methylaminomethyl)indole (1.5 g, 8 mmole), from Preparation 40, and Et3N (1.12 mL, 8 mmole) in CH2Cl2 (75 mL) at 0° C. was added acryloyl chloride (0.65 mL, 8 mmole) dropwise over 5 minutes. The reaction was stirred at 0° C. for 1 hr then was poured into ice water. The organic phase was separated, washed with brine, dried (MgSO4), and concentrated to dryness to give the title compound (1.7 g, 90%) as a yellow oil. This was used without further purification: TLC silica gel (50% EtOAc/hexanes) Rf=0.41.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.[OH-].[Na+].[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>O.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: C=C(C)C(=O)Cl
Reactant: Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Yield: 40 %

Procedure:
To a solution of BDHN or 2(2,7-dihydroxynaphthyl) 2H-benzotriazole (5.0 g 18 m mol) and NaOH (0.8 g, 20 m mol) in water (100 ml) a solution of methacryloyl chloride (20 m mol, 4 ml) in chloroform (50 ml) was added dropwise with vigorous stirring. The mixture was stirred for 1 additional hour. The organic layer was separated and washed thoroughly with water before evaporation to yield a crude product that was recrystallized from carbon tetrachloride to give a yellow solid (2.5 g, 40% yield) of 2(2-hydroxy-7-methacryloxynaphthyl) 2H-benzotriazole--m.p. 167°-168° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=1)=[C:24]=[O:25]>>[F:34][C:33]([F:35])([F:36])[O:32][C:28]1[CH:27]=[C:26]([NH:23][C:24]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1cccc(OC(F)(F)F)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(OC(F)(F)F)c1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 1-isocyanato-3-trifluoromethoxy-benzene (intermediate 15) gave the titled compound in 70% yield as white amorphous solid. MS: 513.23 (MH+).