Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:20]([CH3:22])[CH3:21])=[N:17][CH:18]=1>C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:4])[CH2:22][CH:19]1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][O:10][CH3:9])=[CH:18][N:17]=1
Reactant: CC[Zn]CC
Reactant: COCOc1ccc(C=C(C)C)nc1
Solvent: Cc1ccccc1
Solvent: ICI
Product: COCOc1ccc(C2CC2(C)C)nc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Diiodomethane (24.8 ml, 308 mmol) was added dropwise to a solution of diethylzinc (200 ml, 220 mmol) 1.1 M in toluene at 0° C. After the addition, the solution was stirred at RT for 40 minutes and then recooled to 0° C. when 5-(methoxymethoxy)-2-(2-methylprop-1-enyl)pyridine (21.3 g, 110 mmol) in toluene (150 mL) was added dropwise through an addition funnel. The reaction was allowed to come to RT and was stirred 12 hrs before being quenched at 0° C. by the addition of a 10:1 saturated ammonium chloride/ammonium hydroxide aqueous solution. The layers were separated and the aqueous layer was diluted with water and extracted into ethyl acetate. The combined organic layers were washed with 10:1 saturated ammonium chloride/ammonium hydroxide aqueous solution, water, brine, dried over sodium sulfate, and concentrated. The crude product was purified through a plug of silica (10:1 Hexanes/EtOAc) to afford the titled compound. MS m/z: 208.2 (100%, M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1)=[O:1]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(CO)ccc2O1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)N=C(c2ccccn2)c2cc(C=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
Active manganese dioxide (300 mg) was added to a solution of Compound 115 (100 mg) in dichloromethane (3 ml) and the mixture was stirred at room temperature for 1 hour. The insoluble substance was filtered off through celite and the filtrate was distilled off under reduced pressure to obtain 6-formyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (40 mg) (Compound 116). Likewise, Compound 146 was prepared from Compound 145.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=NN)[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:16]([N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CO>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:16]([N:22]1[C:23](=[O:28])[CH:24]2[CH:25]([C:10]2([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:11][CH2:12][CH3:13])[C:26]1=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCN1C(=O)C=CC1=O
Reactant: CCCC(=NN)c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CCC)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-(3-Nitrophenyl)-1-butanone hydrazone (Preparation 63, 1.0 g, 4.8 mmol) was dissolved in dioxan (20 ml) and cooled to 10° C., manganese dioxide (grade CMD-1 from Sumitomo, 10 g, 117 mmol) was added portionwise. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. This suspension was filtered over a pad of Celite® directly into a solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.88 g, 4.5 mmol) in dioxan (20 ml). The Celite® pad was washed with dioxan (125 ml) and then stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo to give a crude orange oil. Methanol (8 ml) was added and the mixture was cooled to 0° C. and upon scratching a white solid precipitated. The solid was filtered off and washed with cold methanol to give the pure product, the mother liquors were concentrated in vacuo and treated again with methanol under the procedure described above to give further product. The title compound was obtained as a white solid (0.28 g, 16%).
Reaction SMILES: [F:1][C:2]1([F:13])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[C:14]([O:18][C:19](=[O:26])[NH:20][C@H:21]1[CH2:24][C@@H:23](O)[CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[C:14]([O:18][C:19](=[O:26])[NH:20][C@H:21]1[CH2:22][C@H:23]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([F:11])[CH:9]=[C:10]3[C:2]([F:1])([F:13])[C:3]2=[O:12])[CH2:24]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Reactant: O=C1Nc2ncc(F)cc2C1(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(F)cnc32)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
3,3,5-Trifluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.248 g, 1.318 mmol), tert-butyl(cis-3-hydroxycyclobutyl)carbamate (0.247 g, 1.318 mmol), and triphenylphosphine (0.519 g, 1.978 mmol) were mixed in THF (5 mL) under an argon atmosphere. The mixture was cooled to 0° C. before diisopropyl azodicarboxylate (0.389 mL, 1.978 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 22 h. The reaction mixture was diluted with sat. NaHCO3 and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.241 g, 0.674 mmol, 51.2% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][CH:31]([N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH2:32][C:33]#[CH:34]>C1COCC1.[Cu]I.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>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:34]#[C:33][CH2:32][CH:31]([N:35]2[C:36](=[O:45])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]2=[O:44])[CH3:30])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCC(C)N1C(=O)c2ccccc2C1=O
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A 100 mL, round-bottom flask containing a mixture of [4-(4-iodophenyl)but-3-ynyl]carbamic acid benzyl ester 23 (2.33 g, 5.75 mmol), CuI (0.22 g, 1.15 mmol), Et3N (10 mL) and THF (anhydrous, 15 mL) was vacuumed and refilled with nitrogen. The procedure was repeated three more time. To the suspension was added Pd(PPh3)2Cl2 (0.40 g, 0.58 mmol) in one portion, followed by a solution of compound 22 (1.35 g, 6.32 mmol) dissolved in THF (anhydrous, 10 mL), which was added dropwise over 2 h. The stirring was continued overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography eluting with a mixture of ethyl acetate (0-25%) and hexanes to afford the desired product 24 (2.60 g, 92%) as an off-yellow solid. 1H NMR (500 MHz, CDCl3) δ 1.71 (d, 3H), 2.61 (t, 2H), 2.92 (m, 1H), 3.14 (m, 1H), 3.43 (t, 2H), 4.67 (m, 1H), 5.07 (br, 1H), 5.11 (s, 2H), 7.12-7.33 (m, 9H), 7.71 (dd, 2H), 7.92 (dd, 1H); m/z (ESI) 491 [C31H26N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][CH:57]([OH:64])[CH2:58][N:59]1[CH:63]=[CH:62][N:61]=[N:60]1>CN(C=O)C>[OH:64][CH:57]([CH2:58][N:59]1[CH:63]=[CH:62][N:61]=[N:60]1)[CH2:56][NH:55][C:29]([C:28]1[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=2)=[O:31]
Reactant: NCC(O)Cn1ccnn1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCC(O)Cn2ccnn2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (33 mg, 1.2 eq.), EDAC.HCl (47 mg, 1.2 eq.) and 1-amino-3-[1,2,3]triazol-1-yl-propan-2-ol (30 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.071 mL, 2.5 eq.). After stirring at rt for 2 weeks, the reaction was concentrated, diluted with DCM and several drops of methanol. After standing at rt for one hour, the resulted precipitate was collected by vacuum filtration, washed and dried to give the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(OC(C)(C)C)=O.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:18])=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNCC3)s2)noc1C(F)(F)F
Reaction time: 12 h
Yield: 69 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-Boc-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford intermediate N-Boc protected product as a colorless solid (165 mg, 74%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately ½ volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (131 mg, 69% overall). 1H NMR (D2O) 2.16 (s, 3 H), 3.22 (m, 4 H), 3.87 (m, 4 H), 7.34 (d, J=4.0, 1 H), 7.42 (d, J=4.0, 1 H). 19F NMR −63.6. LC/MS 4.34 min, [M+1]+ 346.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([CH2:14][N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COc1ccccc1NC(=O)CCl
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=O)CN(Cc1ccccc1)Cc1ccccc1
Yield: 82.6 %

Procedure:
To a stirred solution of 28.1 g of 2-chloro-N-(2-methoxyphenyl)acetamide (C.A. 50, 8730i) in 200 ml toluene was added 58.3 g of dibenzylamine and refluxed for 48 hours. After separation of dibenzylamine hydrochloride, the solvent was removed from the reaction mixture. Crystallization of the residue from isopropylether gave 41.9 g colorless crystals of 2-[bis(phenylmethyl)amino]-N-(2-methoxyphenyl)acetamide, mp 92°-94°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:20][C:19]1[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=1)=[O:6]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1O
Yield: 44.7 %

Procedure:
Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:28]2[CH2:27][CH2:26][CH:25]([O:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Clc1ccc(CCOC2CCNCC2)cc1
Product: C[C@](O)(CN1CCC(OCCc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 71.4 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.076 g, 0.350 mmol) and 4-[2-(4-chlorophenyl)ethoxy]-piperidine (0.080 g, 0.334 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-{4-[2-(4-chlorophenyl)ethoxy]-piperidin-1-yl}-2-methyl-propan-2-ol (0.109 g, yield 71%) as a light yellow oil in the same manner as in Example 254.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([C:12]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:13]([CH3:22])[C:14]=2[C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>CN(C)C=O.O1CCCC1.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:12]2[N:11]3[C:15]([CH:16]=[CH:17][C:9]([OH:8])=[CH:10]3)=[C:14]([C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH3:22])=[O:35])=[CH:25][C:26]=1[O:33][CH3:34]
Reactant: [H][H]
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2cc(O)ccc12

Procedure:
100 mg of Pd/C (10%) are added to 1.0 g (2.17 mmol) of methyl [6-(benzyloxy)-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate in suspension in 30 mL of dimethylformamide and 30 mL of tetrahydrofuran. The reaction mixture is stirred at 10 bar of hydrogen for 48 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(C)([O-])C.[K+].C(S[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[N:19]=1)C>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[N:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCSc1nc(-c2ccc(OC)c(OC)c2)cc2nccn12
Reactant: Nc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc3nccn3c(Nc3cccc(F)c3)n2)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of m-fluoroaniline (88.90 mg, 0.8 mmol) in 1.5 ml of dry DMSO was added, potassium tert-butoxide (94.26 mg, 0.84 mmol), and 5-ethylsulfenyl-7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin (126.16 mg, 0.4 mmol). The resulting solution was stirred overnight and 3 ml of ice water was added. The produced precipitate was collected by filtration, and washed with water, 2-propanol, and ether to give crude product of (3-fluorophenyl)-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-yl]amine. The crude product was purified by preparative TLC to give the pure product (127.000 mg, 87.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>C(Cl)Cl.CC(O)C>[NH2:30][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: Fc1c(OCc2ccccc2)cccc1-c1nc(C2CCC2)n2ccnc(Cl)c12
Reactant: N
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 125 °C
Yield: 75 %

Procedure:
1-(3-Benzyloxy-2-fluoro-phenyl)-8-chloro-3-cyclobutyl-imidazo[1,5-a]pyrazine (500 mg, 1.2 mmole) in methylene chloride was placed in a Parr pressure reactor, cooled in ice salt bath and charged with a saturated solution of NH3 in 2-propanol (10 mL). The pressure reactor was heated at 125° C. overnight. The reaction was cooled to room temperature and the crude reaction mixture was evaporated and triturated with methylene chloride and filtered. The filtrate was evaporated to dryness and purified by silica-gel column chromatography [eluant CH2Cl2:hexane (70:30)] to afford the title compound (350 mg, 75%); FAB-MS: m/z 388.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1nc(Cc2ccc([N+](=O)[O-])cc2)no1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Product: Cc1nc(Cc2ccc(N)cc2)no1
Yield: 9.8 %

Procedure:
A mixture of 5-methyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole (3.89 g), Lindlar catalyst (2.0 g) and tetrahydrofuran (200 mL) was subjected to catalytic reduction under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]aniline as a brown oil (0.33 g, yield 10%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:12]2)=[C:5]([F:29])[CH:4]=1)#[N:2].C(OCC)C.[ClH:35]>O1CCOCC1>[ClH:35].[F:29][C:5]1[CH:4]=[C:3]([CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCCOc3ccc(C#N)cc3F)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 7-[3-(4-cyano-2-fluorophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (9.15 g, 22.5 mmol; see step (ii) above) was taken in 15 mL of dioxane, to which was added 75 mL of diethyl ether saturated with HCl gas. The resulting mixture was stirred for 1 h at RT under a nitrogen atmosphere before solvent was decanted and the precipitated solid washed with dry diethyl ether (4 times) and dried under vacuum. This gave 9 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH2:40][C@H:41]([O:43][CH3:44])[CH3:42])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>C1COCC1>[OH:26][C@@H:27]([CH2:38][O:39][CH2:40][C@H:41]([O:43][CH3:44])[CH3:42])[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29]
Reactant: CO[C@H](C)COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@H](C)COC[C@H](O)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Tetrabutylammonium fluoride (881 μl, 0.88 mmol) was added to (S)-2-(tert-butyldimethylsilyloxy)-3-((R)-2-methoxypropoxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y11) (169 mg, 0.44 mmol) in THF (2203 μl) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (3×10 mL), the organic layer was back washed with water (5 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (64.0 mg, 53.9%). 1H NMR (400 MHz, CDCl3) δ 1.13 (d, 3H), 2.53 (s, 3H), 3.33-3.43 (m, 5H), 3.68-3.82 (m, 2H), 4.04-4.11 (m, 1H), 4.33 (t, 1H), 4.53 (s, 1H), 8.12-8.15 (m, 1H), 9.19 (s, 1H), 9.43 (d, 1H); m/z (ESI+) (M+H)+=270.24; HPLC tR=1.04 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([N:22]=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1.O.C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[C:21]([NH2:22])=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N=O)c(OC)nn12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cc(C)cc(C)c1-c1cccc2c(N)c(OC)nn12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine (200 mg) was suspended in ethanol (10 mL), and then water (5 mL), acetic acid (0.5 mL) and zinc powder (200 mg) were added and the mixture was heated and stirred at 60° C. for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain 2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridine-3-amine as a crude product. This was dissolved in tetrahydrofuran (5 mL) without purification, and after adding cyclopropanecarboxyaldehyde (0.166 mL) and 3 M aqueous sulfuric acid (0.739 mL), sodium borohydride (56 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (240 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]2[C:20]=1[Cl:24]
Reactant: COC(=O)c1c(O)c2cc(Cl)c(Cl)n2n(Cc2ccc(F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)c(Cl)n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6,7-Dichloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 428 (M+H)+.