Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:24])=[C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(O)C>[CH3:24][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:9][C:8]=1[NH:10][C:11]1[O:12][C:13]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C)c(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)CCc2ccccc2)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (100 mg, 0.315 mmol) and benzaldehyde (0.035 mL, 0.35 mmol) in ethanol, was added dropwise at 0° C., 1 mL of aqueous NaOH 30%. After the mixture was stirred at room temperature for 16 h and poured into ice water (ca. 10 mL). The precipitate was filtered, washed diethyl ether and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]#[CH:31]>>[C:35]([O:34][C:33](=[O:39])[NH:32][CH2:29][C:30]#[C:31][C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:28]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Reactant: C#CCNC(=O)OC(C)(C)C
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and tert-butyl prop-2-ynylcarbamate were converted to I-39 (31%): HRMS Calcd. for C28H29N5O5: 516.2246, Found 516.2244.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=1)C=C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH:6]=[C:5]2[NH2:4])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCNc1cc(NCc2ccccc2OC)nc2ccc(Cl)cc12
Reactant: NCc1ccccc1
Product: COc1ccccc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=385.3 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline-2,4-diamine and benzylamine
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]([C:5]([OH:7])=O)[CH3:4].C(N1CCOCC1)C.ClC(OCC(C)C)=O.O1CCCCC1ONC([C@H]([C@@H:51]([CH2:60][CH:61]([CH3:63])[CH3:62])[C:52]([NH:54][NH:55][CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])C/C=C/C1C=CC=CC=1)=O>O1CCCC1.C(OCC)(=O)C>[CH2:56]([N:55]([C:5](=[O:7])[C@H:3]([CH3:4])[N:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:54][C:52](=[O:53])[CH2:51][CH2:60][CH:61]([CH3:63])[CH3:62])[CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.233 g of N-methyl-N-tert.-butoxycarbonyl-L-alanine in 10 ml of tetrahydrofuran was cooled to −10° C. and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for a further 10 minutes at −10° C. and then treated with 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0° C. and stirring was continued for 45 minutes. The mixture was then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.608 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(N-methyl-N-tert.-butoxycarbonyl-L-alanyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:21][N+:18]([O-:20])=[O:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(CC[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
In a 1 l. r.b. flask 100 g. (0.6 mole) of 3,4-dimethoxybenzaldehyde, 40 g. (0.52 mole) of ammonium acetate, 50 ml. (0.93 mole) of nitromethane, and 400 ml. of glacial acetic acid were combined and refluxed for 2 hours. The solution was then cooled to room temperature overnight. Yellow crystals were then collected via suction filtration and washed with hexane and ether. 73 g. of desired product were collected with m.p. 133°-134° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:30]3[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][O:13]1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCC2OCCc3ccccc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC2OCCc3ccccc32)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 94.8 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-isochroman-1-ylmethyl-amine (141 mg, 0.46 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (125 mg, 0.6 mmol), and Cs2CO3 (0.37 g, 1.15 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (27 mg, 0.023 mmol) at room temperature. The mixture is heated at 85° C. for 3 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The aqueous layer is separated, acidified to pH 2.5 with 1M HCl solution, and extracted with EtOAc (2×30 mL). The extracts are dried (MgSO4), filtered through a short pad of SiO2 to afford 2-(3-{6-[(isochroman-1-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (189 mg, Example 91). LCMS: RT=2.03 minutes; MS: 434 (M+H); 1H NMR (300 MHz, CDCl3) □9.8 (1H, s), 8.02 (1H, s), 7.82 (1H, d, J=6 Hz), 7.5-7.1 (6H, m), 6.43 (1H, s) 5 (1H), 4 (3H, s), 3.85-3.75 (1H, m), 3.65-3.55 (1H, m), 3.04-2.95 (1H, m), 2.75 (1H), 1.8 (6H, s). IC50=23 nM
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.BrBr>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=NN1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Yield: 93.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-4,5-dihydropyridazinone (11.75 g) and glacial acetic acid (100 ml) was added dropwise 3 ml of bromine and the mixture was heated at 60°-70° C. for 3 h. The resulting mixture was cooled and slowly poured into 400 ml of cold water. The resulting white solid was filtered and dried to yield 10.83 g (89%) of 6-(4-chlorophenyl)pyridazinone.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][C@H:8](O)[CH2:9][C@H:3]1[CH2:4][CH2:5]2.S(Cl)([Cl:13])=O.[OH-].[Na+].C(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][CH:8]1[CH2:9][CH:3]2[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]2)[CH2:7]1
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Reactant: O=S(Cl)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN1C2CCC1CC(Cl)C2
Reaction time: 8 h

Procedure:
To a solution of 95 g pseudotropine in 420 ml abs. CHCl3 are added dropwise at 0° 195 ml thionyl chloride within 20 minutes. The reaction mixture is refluxed for 4 hours, then left overnight at room temperature and then heated to 60°-65° for 3 hours. The mixture is then diluted with CH2Cl2 to a volume of ca. 100 to 150 ml and poured on ice-water. A 35% aqueous NaOH solution is added to a pH 11 and then dry ice to a pH 10. After extraction with CH2Cl2 and distillation of the extracts (second fraction~97°-98°) the title compound is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH:3](Cl)[CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([C:5]1[O:9][CH2:13][CH2:12][S:11][C:4]=1[CH2:3][CH2:2][Cl:1])[CH2:7][CH3:8]
Reactant: CCCC(=O)CC(Cl)CCl
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1=C(CCCl)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 0.056 mole (10 g.) of 1,2-dichloro-4-heptanone and 0.06 mole (5 g.) 2-mercaptoethanol was stirred in 200 ml toluene; 0.06 mole (6 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and refluxed with 0.5 mole PTS, using a Dean-Stark trap to remove water for 7 hours. The PTSA solution was washed with 5% sodium bicarbonate, dried, filtered and the solvent was removed. The product was distilled; bp 80°-85°/0.05 mm. Yield 23%.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)OC1CCN(CC#CCN(C)C(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(C)CC#CCN1CCC(O)C1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 820 mg of (racemic)-N-[4-[3-(acetyloxy)-1-pyrrolidinyl]-2-butynyl]-N-methyl acetamide, 635 mg of sodium carbonate and 40 ml of methanol was stirred overnight. An equal volume of dichloromethane was added, the mixture filtered and the solvents concentrated. This residue was purified by chromatography (alumina), giving 500 mg of the desired product as a yellow oil.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC)=O.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CC(C)=O>[CH2:22]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNCCCC
Reactant: CC(=O)CCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCN(CCCC)C(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
A! A solution of 100 g (0.86 mole) of levulinic acid in 1 l of acetone was added with 118 ml (0.86 mole) of triethylamine, and stirred for 15 minutes at room temperature. The mixture was cooled to 5° C. and added with a solution of ethyl chloroformate (83.3 ml, 0.86 mole) in 500 ml of acetone, then stirred for 15 minutes. The solid was filtered off and the mother liquor was added to a solution of dibutylamine (180 ml, 1 mole) in 1 l of acetone, then stirred overnight at room temperature, evaporated to dryness under vacuum, and the residue was dissolved in 1 l of ethyl ether, washed with 400 ml of 0.5N HCl, then with 400 ml of 0.5N sodium hydroxide. The ether phase was anhydrified over sodium sulfate and evaporated to dryness thus providing 175.5 g of a crude which by distillation under vacuum gave 112.5 g (yield: 57%) of N,N-dibutyl-4-oxo-pentanamide (b.p. 135°-138° C./1 mmHg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N>[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH:20][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
N,N-Diisopropylethylamine (3 mL, 17.16 mmol) was added to a solution of (trans)-2-phenylcyclopropanamine hydrochloride (1.5 g, 8.58 mmol) in 70 mL of CH3CN. After complete dissolution of the amine the methyl 2-bromoacetate (930 μL, 9.44 mmol) was added and then stirred overnight at room temperature. After solvent removal the crude was purified by flash chromatography eluting with CH2Cl2/MeOH (99:1 to 90:10) to get methyl 2-((trans)-2-phenylcyclopropylamino)acetate as colourless oil (1.76 g, Yield=100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:22]([O:29][C:30]([N:32]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:33]([CH2:35][CH3:36])[CH3:34])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:40]2[CH2:39][CH2:38][CH:37]([N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH:33]([CH2:35][CH3:36])[CH3:34])[CH2:42][CH2:41]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)N(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)N(C(=O)OCc1ccccc1)C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 80.7 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 24 mg of 4-(N-(benzyloxycarbonyl)-N-secbutylamino)piperidine-hydrochloride, 0.013 mL of DIEA and 24 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 32 mg of the title compound. HPLC (YMC "Octyl" 4.6×250 mm column, 60:40 v/v H2O/CH3CN+0.5% TFA, 1.5 mL/min, 200 nm): Retention Time: 12.99 min. 1H NMR (300 MHz, CDCl3): δ0.70-0.82 (m, 3H), 1.16 (t, J =6.4 Hz, 3H), 1.37-1.95 (m, 10H), 2.34-2.66 (m, 6H), 2.83-2.99 (m, 4H), 3.69 (ABq, J =13 Hz, 2H), 5.11 (s, 2H), 7.14-7.39 (m, 15H). Mass Spectrum (ESI): 540.6 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:14][C@H:13]([NH2:15])[CH2:12]3)[S:9][C:5]=2[CH:4]=1.Cl[C:19]1[C:24]([N:25]([CH3:30])[C:26](=O)[O:27]C)=[CH:23][CH:22]=[CH:21][N:20]=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:12][C@H:13]([N:15]4[C:19]5=[N:20][CH:21]=[CH:22][CH:23]=[C:24]5[N:25]([CH3:30])[C:26]4=[O:27])[CH2:14]3)[S:9][C:5]=2[CH:4]=1
Reactant: N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Reactant: COC(=O)N(C)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccc(F)cc4s3)C2)c2ncccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120° C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100° C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1 H), 7.49 (dd, J=8.90, 4.79 Hz, 1 H), 7.32 (dd, J=8.12, 2.64 Hz, 1 H), 7.17 (dd, J=7.73, 1.27 Hz, 1 H), 6.97-7.07 (m, 2 H), 5.90 (br. s., 1 H), 5.33-5.50 (m, 1 H), 4.48-4.74 (m, 1 H), 3.48-3.67 (m, 2 H), 3.43 (s, 3 H), 2.34-2.63 (m, 2 H).
Reaction SMILES: [OH:1][CH2:2][C:3]12[N:10]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][O:5][CH2:4]2.[CH3:17]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]12[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][O:5][CH2:4]2)=[O:1]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)OC(=O)N1C2CCC1(CO)COC2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1(C=O)COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of isopropyl 5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (73 mg, 0.3 mmol) in DCM (mL) was added Dess-Martin (191 mg, 0.45 mmol) at ice-bath. The mixture was allowed to warm to room temperature while stirred for 2 h. Then the mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3 (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 5-formyl-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (71 mg, 98%) which was used for next step without further purification. MS: calc'd (MH+) 242, measured (MH+) 242.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:34])([F:33])[F:32])[N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([CH:15]3[CH:19]([OH:20])[CH2:18][N:17]([C:23]4[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:33])([F:34])[F:32])[N:24]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1nc(C(F)(F)F)nc(Cl)c1C
Reactant: O[C@@H]1CNC[C@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nc(N2CC(O)C(N3CCC(O)(c4ccc(Cl)cc4)CC3)C2)c1C

Procedure:
The title compound was prepared following general procedures described above from trans-4-(4-chloro-phenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol hydrochloride and 4-chloro-5,6-dimethyl-2-trifluoromethyl-pyrimidine in the presence of diisopropylethylamine and DMF. 1H-NMR (300 MHz, DMSO): δ 1.58 (2H, m), 1.89 (2H, m), 2.40 (3H, s), 2.60 (3H, m), 2.95 (2H, m), 3.32 (1H, m), 3.44 (1H, m), 3.80 (2H, m), 4.32 (1H, m), 4.90 (1H, s), 5.20 (1H, d), 6.92 (1H, s), 7.42 (4H, dd). Retention Time (LC, method, AA standard): 1.75 min. MS (M+H+): 457
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[CH2:18])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1
Reactant: C[Mg+]
Reactant: O=C1c2ccccc2COc2cc(F)ccc21
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2ccccc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Cool a solution of 3-fluoro-6H-dibenzo[b,e]oxepin-11-one (prepared according to the procedure reported by M Kurokawa, F Sato, Y Masuda, T Yoshida and Y Ochi, Chem. Pharm. Bull., 1991, 39(10), 2564-5273; 11.5 g, 50.5 mmol) and THF (100 mL) to 0° C. under N2. Add dropwise MeMgBr (3.0M in Et2O, 33.7 mL, 101 mmol) this mixture. Warm to room temperature and stir overnight. Cool to 0° C. and quench very carefully (exotherm) with HCl (4.00 M in dioxane, 30 mL). Warm to room temperature and stir for 30 min. Dilute reaction mixture with water (70 mL) and extract into ethyl acetate (three 100 mL portions). Dry (MgSO4), filter, and concentrate organics to a brown solid. Purify crude product on a 100 g plug of silica gel, eluting with hexanes to afford 9.26 g (81%) of the title compound as a yellow solid. MS [EI] 226; HPLC shows 90% purity.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:6](=[CH:5][CH2:4][CH2:3][N:2]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:1])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CBr
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 2.61 g of 5-[3-(methylamino)propylidene]-5H-dibenzo[a,d]cycloheptene, 2.00 g of ethyl bromoacetate, 1.38 g of potassium carbonate, and 13 ml of N,N-dimethylformamide was stirred at 70° C. for 4 hours. After the reaction was completed, water was added to the reaction mixture and the mixture was then extracted with diethyl ether. The ether layer was washed with water and dried, and then the solvent was removed by distillation. The residue was purified by column chromatography on aluminum oxide [n-hexane-diethyl ether (1:1)] to give 1.88 g of slightly yellow viscous liquid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].[OH-].[K+]>O1CCOCC1.CO>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4]2)=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl 2,6-naphthalenedicarboxylate (39.6 g, 162 mmol) in dioxane (1.2 L) was heated to 70-80° C., slowly treated with a solution of KOH (9.1 g, 162 mmol) in methanol (162 mL), heated to 70° C., stirred for 30 minutes, cooled to room temperature, and filtered. The solid was washed sequentially with dioxane and diethyl ether, dissolved in water, adjusted to pH<7 with 1M HCl, and filtered. The solid was washed with water and dried to provide the desired product.