Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12]([Cl:14])=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(OCC)(=O)C>[BrH:16].[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Br:16])([Cl:14])[CH2:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:16]
Reactant: BrBr
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Solvent: CCOC(C)=O
Product: Br
Product: ClC1(CBr)CN=C(SCc2ccccc2)S1
Temperature: 0.5 °C
Reaction time: 0.33 h

Procedure:
Under a slight stream of nitrogen, 19.9 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester are placed in 100 ml of ethyl acetate and cooled to 0-1° C. During the addition of bromine, the apparatus is flushed thoroughly with nitrogen. 14.0 g of bromine are added in the course of 40 minutes in such a manner that the temperature can be maintained at 0-10° C. When the addition is complete, stirring is carried out for about 20 minutes. The reaction mixture is concentrated in vacuo at 20-250C. 50 ml of hexane are added, the mixture is filtered at 20-25° C., and the filtration residue is washed with 40 ml of hexane and dried in vacuo at room temperature. The title product is obtained in the form of the hydrobromide (compound 2.1).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylpropane-1,3-diamine according to general procedure 1 providing the intermediate (160 mg, 84%) as a clear oil: Rf=0.16 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.5 Hz, 1H), 3.40 (t, J=7.1 Hz, 2H), 2.48-2.45 (m, 2H), 2.27 (s, 6H), 1.93-1.88 (m, 2H); ES-MS: (M+H)=298, 300 m/z.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1.ClCCl>[C:33]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cc(NC(=O)c2cccnc2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To 0.15 g (0.328 mmol) 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.058 g of nicotinoyl chloride hydrochloride, 0.091 cm3 of triethylamine and 8 mg of 4-dimethylaminopyridine. After stirring for 16 hours at reflux, the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 148 mg of a beige-coloured solid, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (82/9/9 by volume)]. After concentrating the fractions under reduced pressure, 0.01 g of 4-nicotinoyl-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide is obtained in the form of a yellow solid; ES+: m/z=527: [M+H]+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:24])=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(C(C)C)C(C)C)C.[NH2:34][C:35]1[N:40]=[C:39]([O:41][C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[NH:47][CH2:46][CH2:45]3)[CH:38]=[CH:37][N:36]=1>C(Cl)Cl.C1COCC1.C([O-])(O)=O.[Na+]>[Cl:24][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2]([N:47]2[C:48]3[C:44](=[CH:43][C:42]([O:41][C:39]4[CH:38]=[CH:37][N:36]=[C:35]([NH2:34])[N:40]=4)=[CH:50][CH:49]=3)[CH2:45][CH2:46]2)=[O:4])=[CH:19][C:18]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nccc(Oc2ccc3c(c2)CCN3)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(c2)CCN3C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
90 mg (0.30 mMol) triphosgene are dissolved in 5 ml ice-cooled CH2Cl2. Then a solution of 148 mg (0.76 mMol) 5-amino-2-chloro-benzotrifluoride and 0.3 ml (1.72 mMol) EtN(iPr)2 in 5 ml CH2Cl2 is added during 15 min. After stirring the reaction mixture for further 15 min, a solution of 200 mg (0.88 mMol) 5-(2-amino-pyrimidin-4-yloxy)-2,3-dihydro-1H-indole (Step 26.2) and 0.3 ml (1.72 mMol) EtN(iPr)2 in 5 ml THF is added. After 16 h at rt, the mixture is diluted with 10% NaHCO3 solution and CH2Cl2, the aqueous phase separated off and extracted twice with CH2Cl2. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; 1% MeOH in CHCl3) gives the title compound: MS: [M+1]+=450; HPLC: EtRet=3.7.
Reaction SMILES: Cl.O1[CH2:7][CH2:6]OCC1.[C:8]1([CH3:49])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28]([C:30]34[CH2:39][CH:34]5[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]5)[CH2:31]3)[CH2:37]4)=[O:29])[CH2:20][CH:19]([NH:40][C:41](OC(C)(C)C)=[O:42])[C:18]2=[O:48])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>C(O)C>[C:8]1([CH3:49])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28]([C:30]34[CH2:37][CH:36]5[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]5)[CH2:31]3)[CH2:39]4)=[O:29])[CH2:20][CH:19]([NH:40][C:41]([NH:17][C:23]3[CH:22]=[CH:27][CH:26]=[C:6]([CH3:7])[CH:24]=3)=[O:42])[C:18]2=[O:48])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(NC(=O)NC2CN(C(=O)C34CC5CC(CC(C5)C3)C4)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
4N HCl-dioxane (5.0 ml) was added to 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (400 mg) in anhydrous ethanol (15 ml), and the mixture was stirred at 50° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine. Subsequently, this compound was dissolved in anhydrous tetrahydrofuran (10 ml), and m-tolyl isocyanate (0.10 ml) was added to thereto. The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure. A solvent mixture of isopropyl ether and ethanol was added thereto for solidification and collection by filtration, to thereby obtain 394 mg of the title compound (yield: 93.1%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:23])[CH3:22])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)[CH3:2].[NH4+:28].[OH-]>C(COC)OC>[CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:23])[CH3:22])=[CH:8][N:7]=[C:6]([NH2:28])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(S(C)(=O)=O)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: CCNc1nc(N)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Temperature: 145 °C
Yield: 47 %

Procedure:
To ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methanesulfonyl-pyrimidin-4-yl]-amine (0.078 g, 0.2 mmol) in microwave reactor vial was added 2.0 mL dimethoxy ethane and 0.5 mL concentrated NH4OH. The vial was capped and placed in a microwave reactor. The internal temperature was warmed to 145° C. After 2 hours an additional portion of 0.4 mL concentrated NH4OH was added and the mixture was heated an additional 2 hours. The mixture was cooled and concentrated in vacuo. Purification via flash chromatography (96:4 CH2Cl2/MeOH) afforded N*4*-ethyl-5-(2-isopropyl-4,5-dimethoxy-benzyl)-pyrimidine-2,4-diamine (0.031 g, 47%) as a pale yellow solid; Mass Spec M+H=329. Use of different alkyllithium reagents in step 1 and/or different substituted amines in steps 6 and 8 of the above procedure afforded additional compounds under the same or very similar reaction conditions. Additional compounds made by the procedure of Example 3 are shown in Table 1.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH:20][CH2:21][CH2:22][CH3:23])[CH:17]([CH3:19])[CH3:18]>C(O)C>[CH2:16]([N:20]([CH2:21][CH2:22][CH3:23])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCNCC(C)C
Solvent: CCO
Product: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 92.7 %

Procedure:
To a solution of ethyl 4-fluoro-3-nitrobenzoate (7.4 g, 0.035 mol) in ethanol (100 mL) was added N-isobutyl-N-propylamine (11.98 g, 0.104 mol) at RT. The reaction mixture was heated at 60° C. for 12 h. It was then concentrated under reduced pressure. The residue was dissolved in water (40 mL) and was acidified to pH=4 with 1 M HCl solution. It was extracted with EtOAc (2×75 mL). The combined organic phases were washed with brine, dried over sodium sulphate and evaporated to afford the title compound (10 g, 93%) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.92 (m, 1H), 7.38 (m, 1H), 4.28 (m, 2H), 3.15 (m, 2H), 3.03 (m, 2H), 1.86 (m, 1H), 1.51 (m, 2H) 1.28 (m, 3H), 0.78 (m, 9H). LC/MS (Method A): 309.0 (M+H)+. HPLC (Method B) Rt 5.05 min (purity: 99.4%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([Br:11])=[CH:9][N:10]=2)[N:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>CS(C)=O>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(Br)n3n2)CC1
Temperature: 100 °C

Procedure:
To 6-chloro-3-bromoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0 equiv) and p-TSA (818 mg, 4.30 mmol, 1.0 equiv) in DMSO (7.00 mL) was added trans-4-aminocyclohexanol (1.49 g, 12.9 mmol, 3.0 equiv). The mixture was heated at 100° C. for 24 h. Purification by column chromatography using 5% methanol in dichloromethane elution gave 1.1 g of the yellow solid, 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.N1CC[C@H:38]([OH:41])C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH2:33][C@@H:38]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)N1CC[C@@H](O)C1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (10 mg, 0.030 mmol, prepared as described in Example 8) was added CDI (10 mg, 0.06 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (5 mg, 0.06 mmol) was added in one portion. The reaction was stirred at ambient temperature for 20 hours before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a solid (9 mg, 67% yield). MS (apci) m/z=445.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1.ClC1C=CC(Cl)=CC=1CCl.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:31][CH:32]=1
Reactant: ClCc1ccc(OCc2cc(Cl)ccc2Cl)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: ClCc1cc(Cl)ccc1Cl
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1,4-dichloro-2-chloromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 265 (M−237).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Reaction time: 2.5 h

Procedure:
A solution of 1.6 ml of 2-methylaminoethanol in 10 ml of water was added dropwise over a period of 5 minutes to a suspension of 6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (prepared as described in Da Re, P. et al., J. Med. Pharm. Chem. 2: 263 (1960)) and 1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2.5 hours at 20°-25° C., the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes, and was then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of a 1.4% sodium carbonate solution, stirred for 30 minutes at 20°-25° C. and diluted by addition of 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5N hydrochloric acid and then with water. The solution was dried on anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo. The resulting oil was taken up in 200 ml of diethyl ether and stirred for 2 hours at 20°-25° C. The solid was collected by filtration and crystallized from ethyl acetate to give 2.97 g of the title compound, melting point 128°-130° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[ClH:35].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[N:10]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2Cc1ccccc1
Product: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CN2Cc1ccccc1

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 71 from 1-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([O:6]C)=[O:5].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[F:1][C:2]1[CH:11]=[C:10]([CH:12]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=O
Reactant: COC(=O)c1c(O)cc(C=O)cc1F
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(O)c(C(=O)O)c(F)c2)N1
Temperature: 40 °C
Reaction time: 3 h
Yield: 13.3 %

Procedure:
To a solution of methyl 2-fluoro-4-formyl-6-hydroxybenzoate (Intermediate 83) (150 mg, 0.76 mmol), 1,2-diphenylethanone (150 mg, 0.76 mmol) and urea (144 mg, 2.4 mmol) in ethanol (5 mL) was added conc. HCl (0.2 mL) and the reaction mixture was refluxed under N2 overnight. Removed solvent in vacuo and the residue (320 mg) was used without further purification. A mixture of this intermediate compound (320 mg) and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL) was stirred at 40° C. for 3 hours. The resulting mixture was cooled and acidified with aqueous HCl (2 M, 12 mL) and a standard aqueous/EtOAc workup was followed. Purification by prep-HPLC (0.1% TFA as additive) gave Compound 158 as a yellow solid (41 mg, two step yield 13%). 1H NMR (CD3OD 400 MHz): δ 7.30-7.20 (m, 5H), 7.10-7.05 (m, 3H), 6.91-6.88 (m, 2H), 6.75 (s, 1H), 6.65 (d, J=11.6 Hz, 1H), 5.29 (s, 1H). MS (ESI): m/z 405.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[C:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CC(=O)c1cccc(C2=NCC(=O)N(C)c3ccc(-c4ccccc4)cc32)c1
Yield: 31 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-acetylphenyl boronic acid. The title compound (44 mg) was obtained as a beige solid, (yield=31%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[NH4+:17]>>[NH2:17]/[C:3](/[C:2]([F:12])([F:11])[F:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Product: CCOC(=O)/C=C(\N)C(F)(F)F
Temperature: 85 °C

Procedure:
To a stirred ethyl trifluoroacetoacetate (87.8 g, 0.48 mol) at 85° C., ammonium acetate (74 0 g, 0.96 mol) was added in portions over 1 hour such that efficient stirring of the mixture was maintained. The mixture was heated at 85° C. for an additional 4 hours. After this period, GC analysis of the reaction mixture showed that the all the ethyl trifluoroacetoacetate had been consumed and the yield of ethyl 3-amino-4,4,4-trifluorocrotonate was greater than 98%.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1.CO>[ClH:1].[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:23][NH:22][CH2:21]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NCC1CNC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.7 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (3.90 mL, 15.6 mmol) was added to a solution of tert-butyl 3-({[(benzyloxy)carbonyl]amino}methyl)azetidine-1-carboxylate obtained in Example (233a) (560 mg, 1.75 mmol) in 1,4-dioxane/methanol (8 mL/8 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated to obtain 448 mg of 3-({[(benzyloxy)carbonyl]amino}methyl)azetidine hydrochloride (100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH2:30]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11](=[N:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)C(C)C)(C)C.O>ClCCl>[C:2]1([C:1]2[O:8][N:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.219 mL; 1.89 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried and concentrated under reduced pressure. The residue was refluxed in a sealed tube with pyridine (6 mL) for 20 hours and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.239 (60%) of ethyl 5-phenyl-1,2,4-oxadiazole-3-carboxylate as a yellow solid.