Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[O:9][C:8]([C:10]([Cl:12])=[O:11])=[N:7][N:6]=1)[CH2:2][CH3:3].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>>[ClH:12].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][N:31]([C:10]([C:8]3[O:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6][N:7]=3)=[O:11])[CH2:30][CH2:29]2)[N:15]=1
Reactant: CCCSc1nnc(C(=O)Cl)o1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: CCCSc1nnc(C(=O)N2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)o1
Product: Cl

Procedure:
The title compound was prepared from 5-n-propylthio-1,3,4-oxadiazole-2-carbonyl chloride (1.68 g., 8.16 mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.36 g., 8.16 mmole) following the procedure of Example 1. The product had a M.P. of 230°-245° C. with decomposition.
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]([NH:13][C:14]2[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)[N:15]=2)[CH2:3]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:20][C:19]1[C:14]([NH:13][CH:4]2[CH2:5][CH2:6][C:7]3([CH2:8][CH2:9][N:10]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:11][CH2:12]3)[CH2:2][CH2:3]2)=[N:15][C:16]([NH:21][C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)=[N:17][CH:18]=1
Reactant: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)c1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)c1
Reaction time: 2 h
Yield: 28.8 %

Procedure:
To a solution of N4-(9-azaspiro[5.5]undecan-3-yl)-5-chloro-N2-(1-methylimidazol-4-yl)pyrimidine-2,4-diamine hydrochloride (200 mg, 0.4850 mmol), 2-cyanoacetic acid (41.6 mg, 0.489 mmol) and TEA (98.4 mg, 0.972 mmol) in a mixture of DCM and DMF (8 mL/2 mL) were added HOAT (99.6 mg, 0.732 mmol) and EDCI (138.7 mg, 0.724 mmol). The reaction was stirred for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a light yellow solid (61.8 mg, 28.8%).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@:4]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:17][CH:18]=2)[CH3:12])[C:6](=[O:28])[NH:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reactant: Cn1ccc(Br)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 130 °C
Yield: 39.1 %

Procedure:
(S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (10 mg, 0.02 mmol), 4-bromo-1-methylpyridin-2(1H)-one (7.6 mg, 2 equiv.), Pd(PPh3)2Cl2 (1 mg, cat. amount), 2M aq Na2CO3 solution (200 μL, excess), and 1,4-dioxane (2 mL) were mixed. The mixture was evacuated and refilled with Nitrogen gas 3×, before being heated to 130° C. in the microwave oven for 2 h. After being cooled down, the mixture was concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (3.7 mg, 38%). LC-MS Method 1 tR=1.53 min., m/z 474 (M+1); H1 NMR (CD3OD) δ 7.63 (d, 1H), 7.51 (d, 2H), 7.43 (d, 2H), 7.32 (t, 2H), 7.22 (t, 1H), 7.14 (d, 2H), 6.74-6.59 (m, 2H), 5.42 (q, 1H), 3.55 (s, 3H), 2.89 (m, 1H), 2.71 (m, 1H), 2.34 (d, 1H), 1.49 (d, 3H), 1.12 (s, 3H), 0.54 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br:11][C:12]1[C:17]2[N:18]([CH3:24])[C:19]([C@@H:21]([NH2:23])[CH3:22])=[N:20][C:16]=2[CH:15]=[CH:14][C:13]=1[F:25].CCN(C(C)C)C(C)C.O>CC(O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:23][C@H:21]([C:19]2[N:18]([CH3:24])[C:17]3[C:12]([Br:11])=[C:13]([F:25])[CH:14]=[CH:15][C:16]=3[N:20]=2)[CH3:22])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C

Procedure:
4-Amino-6-chloropyrimidine-5-carbonitrile (0.88 g, 5.71 mmol) was added to a solution of (S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine (1.11 g, 4.08 mmol) and DIPEA (2.6 mL, 14.7 mmol) in IPA (30 mL) and the resultant mixture stirred at 85° C. for 16 h. The reaction mixture was poured into water and the precipitated solid removed by filtration. The solid was washed with water and dried to give the title compound as an off white solid (1.61 g, 100%). LCMS (Method C): RT 2.68 min [M+H]+ 390.1, 392.1
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13])=[O:6].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.CS(C)=[O:45]>O>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([OH:45])[CH:11]([CH:15]=3)[C:12]([NH2:14])=[O:13])=[O:6])[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(C)=O
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1cc(C(=O)CCCCl)ccc1OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C1C=C(C(=O)CCCN2CCN(c3ccccc3)CC2)C=CC1(O)OCc1ccccc1
Temperature: 90 °C
Yield: 58 %

Procedure:
A mixture of 1 g of 5-(4-chlorobutyryl)-2-benzyloxy-benzamide, 1.2 g of 1-phenylpiperazine, 3.3 ml of triethylamine and 10 ml of dimethyl sulfoxide was heated at 90° C. for 15 hours while stirring. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The thus-produced residue was crystallized from ethyl acetate-ether to obtain 1.6 g of 5-[4-(4-phenyl-1-piperazinyl)butyryl]-2-benzyloxy-salicylamide (yield: 58.0%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[O:14][CH2:15][CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([NH:5][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a mixture of methanesulfonamide (1.0 g, 11 mmol), triethylamine (1.9 mL, 14 mmol), and DMAP (0.13 g, 1.1 mmol) in DCM (20 mL) cooled in an ice-water bath was added ethyl carbonochloridate (1.1 mL, 12 mmol) dropwise via a syringe under an argon atmosphere. The mixture was allowed to warm up to rt overnight. The reaction mixture was concentrated, and the residue obtained was dissolved in EtOAc (100 mL). The solution was washed with 1 N HCl (20 mL) and brine, and dried over MgSO4. The mixture was filtered and concentrated to give compound 12a as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.86 (br. s., 1H), 4.28 (q, J=7.25 Hz, 2H), 3.30 (s, 3H), 1.33 (t, J=7.25 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:33]([C:37]1[CH:38]=[CH:39][C:40](=[C:42]([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>CCOCC.O>[C:33]([C:37]1[CH:38]=[CH:39][CH:40]([C:42]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CC(C)=C1C=CC(C(C)(C)C)=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 1.98 g (7.1 mmol) of 3,6-di-tert-butylfluorene in 40 ml of ether, 4.6 ml (7.5 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.56 g (9.6 mmol) of 3-tert-butyl-6,6-dimethylfulvene in 20 ml of ether was further dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 60 ml of water was added. The separated organic phase was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.35 g of a light yellow solid (yield: 43%). The analyzed values are given below.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cccnc1Cl
Reactant: BrCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2cccnc2Cl)CCCC1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
2-(2-Chloropyridin-3-yl)acetonitrile (0.280 g, 1.835 mmol) was dissolved in dry tetrahydrofuran (1.5 mL) under nitrogen and cooled in an ice bath. 1,4-Dibromobutane (0.220 ml, 1.842 mmol) was added followed by dropwise addition of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.5 ml, 4.50 mmol). The mixture was stirred for 20 minutes then quenched by addition of saturated ammonium chloride (10 mL). Water (100 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 1-(2-chloropyridin-3-yl)cyclopentanecarbonitrile (0.252 g, 1.219 mmol, 66.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Yield: 86.5 %

Procedure:
A mixture of 3.5 g (0.011 mole) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 15.4 ml (0.11 mole) of 1,5-dibromopentane and 1.2 g (0.0087 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone was stirred at reflux for 77 hours. During the reflux period additional 1.4 g portions of potassium carbonate were added at 4, 21, 28 and 45 hours. The solvent was removed in vacuo and the residue was purified by HPLC using 17% ethyl acetate-hexane to yield 4.35 g (84% yield) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 43.4 %

Procedure:
Methyl (3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 mg (43%) of product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[CH3:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14])[NH:8][C:7]2=[O:13]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: CNC(C)(C)C
Solvent: CN1CCCC1=O
Product: CN(c1nc2c(Br)cccc2c(=O)[nH]1)C(C)(C)C
Temperature: 150 °C
Yield: 24.7 %

Procedure:
A mixture of 8-bromo-2-chloroquinazolin-4-ol (407c, 0.20 g, 0.77 mmol) in N-methyl-tert-butylamine (Aldrich; 0.919 mL, 7.71 mmol) and 1 mL NMP was sealed and heated to 150° C. in an oil bath for 6 h. The reaction was heated for 3 days. The reaction was partitioned between sat'd aq. NH4Cl and EtOAc. The organic layer was washed with sat'd aq. NH4Cl once, sat'd aq. NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM, adsorbed onto 1.5 g silica gel, and purified by silica gel chromatography (24 g column) using 0-50% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butyl(methyl)amino)quinazolin-4(3H)-one (0.060 g, 0.19 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (1H, br. s.), 7.76-8.03 (2H, m), 6.95-7.14 (1H, m), 2.97 (3H, s), 1.55 (9H, s). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[C:9]([CH3:18])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O:5][CH3:6])=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:18][C:9]1[C:8]([CH2:7][P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COP(=O)(Cc1cc2ccccc2nc1C)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COP(=O)(Cc1cc2ccccc2nc1CBr)OC
Yield: 61 %

Procedure:
A solution of the obtained 3-(dimethylphosphonomethyl)-2-methylquinoline (0.28 g, 1.0 mmol) in carbon tetrachloride (20 ml) was treated with benzoylperoxide (50 mg) followed by N-bromosuccinimide (0.20 g, 1.1 mmol). The reaction mixture was refluxed for 4 hours, filtered and concentrated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate as the eluent to give 0.21 g of 2-bromomethyl-3-(dimethylphosphonomethyl)quinoline.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:18]C(=O)OC(C)(C)C)[C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[NH2:18])=[CH:5][CH:4]=1
Reactant: C=Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL round bottom flask containing (S)-tert-butyl ((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate (97 mg, 0.256 mmol) was added DCM (3 mL). The resulting mixture was then stirred at 23° C. for 2 min. At this time, TFA was added (3 mL) and the reaction was stirred for 3 h. The solvent was removed, and the material was immediately used with no further purification. MS (ESI pos. ion) m/z: 279.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH:22]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:20]=[CH:19]1>>[CH3:17][N:18]1[CH:22]=[C:21]([S:23]([N:9]2[CH2:10][CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)(=[O:25])=[O:24])[N:20]=[CH:19]1
Reactant: COC(=O)C1(c2ccccc2)CCCNC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: COC(=O)C1(c2ccccc2)CCCN(S(=O)(=O)c2cn(C)cn2)C1

Procedure:
The target was synthesized as in Production Example 1(1), using the raw material methyl 3-phenylpiperidine-3-carboxylate described in literature (Tetrahedron Letters 42 (2001) 1645-1646) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([F:32])=[N:34][CH:35]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1ccc(F)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(F)nc6)cn5n4)c3)c2)CC1
Yield: 19.5 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), 6-fluoronicotinic acid (61 mg, 0.438 mmol), oxalyl chloride (64 μL, 0.730 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (38 mg, 20%) was obtained as a pale-green powder.
Reaction SMILES: [C:1]([O:10]C(OC(C)(C)C)=O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(O)([C:20]([F:23])([F:22])[F:21])=O>>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:20]([F:23])([F:22])[F:21])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)c1ccccc1N
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(trifluoromethyl)aniline (25 g, 0. 15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(O)C)C>CCOCC>[C:20]1([S:26][C:2]2[C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Cl)S1
Reactant: Sc1ccccc1
Agent: CCOC(C)O
Solvent: CCOCC
Product: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Sc2ccccc2)S1
Temperature: 25 °C
Yield: 36 %

Procedure:
2-Chloro-3-(2,4-dioxothiazolidin-5-ylidene-methyl)quinoline and thiophenol (1.2 eq) were mixed with ethoxyethanol and heated to reflux under N2 for 2 hours. The reaction mixture was allowed to cool to RT, ether was added and bright-yellow precipitate was filtered off, washed several times with ether, air dried for 24 hrs at RT to give pure product (Yield-36%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1
Yield: 53 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 1.52 g (7 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 4-methoxy benzoyl chloride separately prepared according to a conventional method, instead of benzoyl chloride, to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.31 g of 4-(4-methoxybenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 53%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[Cl-].[Li+].CN(C=O)C>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 160 °C
Reaction time: 60 h

Procedure:
A mixture of 5,6dimethoxyindan-1-one (25.0 g, 0.13 mole), lithium chloride (20.0 g, 0.47 mole) and DMF (200.0 mL) was stirred at 160° C. for 60 hrs. Water (400.0 mL) was added and the mixture washed with ethyl acetate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (2×300.0 mL). The organic layer was washed with brine and the solvent removed in vacuo. The crude material was purified on a silica gel column using DCM/MeOH(97/3) as the eluent. The solvent was removed in vacuo to yield 5-hydroxy-6-methoxy-indan-1-one (Intermediate H) as a light yellow solid. MS m/z 179 (M+H)+. :179 m/z. The title compound (Intermediate H) is a known compound and may also be prepared by demethylation of 5,6 dimethyoxyindan-1-one using KCN/DMSO at 100° C. (J. M. Saa et al., J. Org. Chem. 1992, 57, 589).