Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.O.NN.NN>[Ni].CO>[NH2:27][C:22]1[CH:21]=[C:20]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH2:1])[CH:5]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(C(c2ccc(O)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100.0 g of 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane, 300 cc of methanol, and 5.0 g of developed NDT-90 (trade name, Raney nickel catalyst, manufactured by Kawaken Fine Chemical Co.) were put into a 500-cc four-neck flask equipped with a thermometer, a Dimroth condenser and a stirrer, and heated, with stirring, up to 60° C. to completely dissolve 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane in the solvent. The resulting solution was kept at 60 to 65° C., to which was dropwise added 78.3 g of an aqueous solution of 60% hydrazine monohydrate over a period of 1 hour. After the aqueous hydrazine solution was added, the mixture was stirred for further 30 minutes, and then gradually cooled to room temperature. After the catalyst was removed through filtration, the reaction mixture was concentrated to obtain a crude product of 2,2-bis(3-amino-4-hydroxy-phenyl)hexafluoropropane. The crude yield was 82.5 g (96.0%). The purity in liquid chromatography was 96.5% (area %).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 43.3 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (80 mg, 210 μmol) and azetidine (42.8 μl, 629 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (38.2 mg, 43.3%) as white solid. MS: m/z=421.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=[O:29]>>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][C:6]1[CH:15]=[C:2]([CH:28]([C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[OH:29])[CH:3]=[CH:4][C:5]=1[O:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 69.5 %

Procedure:
(5-Bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (0.98 g, 3.09 mmol), n-butyl lithium (1.24 ml, 3.09 mmol), and 3,5-dimethoxybenzaldehyde (0.47 g, 2.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-drihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanol as an oil (0.79 g, 69%), HPLC purity was 98.3% at 2.55 min. (90/10 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 6.92-6.78 (m, 3H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.66 (d, J=3 Hz, 1H, CH), 3.78 (s, 3H, single OCH3), 3.76 (s, 6H, 2OCH3), 2.15 (d, J=3 Hz, 1H, OH), 0.97 (s, 9H, 3OCH3), 0.13 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:55][C@@H:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:58][C@@H:57]1[OH:69].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:62]([N:59]1[CH2:60][CH2:61][C@@H:56]([NH:55][C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:13](=[O:14])[C:12]3[CH:29]=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:37][CH2:38]4)=[CH:32][C:11]=3[O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)(=[O:17])=[O:18])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])[C@@H:57]([OH:69])[CH2:58]1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@@H]5CCN(Cc6ccccc6)C[C@@H]5O)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of EXAMPLE 187A (0.158 g), (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049 g), and triethylamine (0.1 mL) in dioxane (2 mL) was heated at 100° C. overnight. The solvent was removed, and the residue was re-dissolved in 1:1 methanol:dimethylsulfoxide (3 mL). It was then purified by reverse phase Prep HPLC. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 20-80% acetonitrile/0.1% TFA in water. The desired fractions were collected, and the organic solvent was partially removed under reduced pressure. The resulting mixture was treated with saturated aqueous NaHCO3 mixture. It was then extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give the desired product. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.77 (dd, 1H), 7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13 (m, 1H), 7.13 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 5.21-5.22 (br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (br s, 4H), 2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (br s, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][C:23](=[O:27])[N:22]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)CO>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[C:12](=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:18]=[C:19]1[CH:21]1[CH2:26][CH2:25][NH:24][C:23](=[O:27])[N:22]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN2C(=O)NCCC2C(=O)Nc2cc(Cl)ccc2C(=O)NCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Cc1ccc(CN2C(=O)NCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
Formula I where R1, R2, R4, R6, R7, R8 and R9 are H, R3 is Chloro; R5 is Benzyl; R10 is p-Methyl-benzyl; and V is N—R′″ where R′″ is H: 3-(4-Methyl-benzyl)-2-oxo-hexahydro-pyrimidine-4-carboxylic acid (2-benzylcarbamoyl-5-chloro-phenyl)-amide (350 mg, 0.713 mmol) was dissolved in 60 mL of ethylene glycol to which was added sodium hydroxide (60 mg, 1.5 mmol). The mixture was stirred at 140° C. for 20 hours and monitored by LC-MS. Following consumption of starting material, the reaction mixture was poured into 100 mL of water. After extraction with DCM, the crude product was purified by flash silica gel chromatography (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the desired product of Formula I, 3-benzyl-7-chloro-2-[3-(4-methyl-benzyl)-2-oxo-hexahydro-pyrimidin-4-yl]-3H-quinazolin-4-one (180 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Br:10])=[CH:8][CH:9]=1)[CH:5]=O.S(O)(O)(=O)=O.[NH2:17][OH:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Br:10])=[CH:8][CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: Cc1c(Br)ccc(Br)c1C=O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1c(Br)ccc(Br)c1C=NO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
10 g (0.42 mol) of 3,6-dibromo-2-methylbenzaldehyde and 178.5 g (0.272 mol) of a 25% strength aqueous solution of hydroxylamine sulfate are mixed in 1.2 l of toluene and heated at 80° C. Over a period of 2 h, 109.2 g (1.36 mol) of 50% strength NaOH are then added dropwise such that the pH is between 3 and 5. Stirring at 80° C. is continued for 1 h, the mixture is stirred at room temperature overnight and the phases are then separated at 80° C. The organic phase is washed once with 350 ml of water. The organic phase is concentrated and the residue is recrystallized from cyclohexane. This gives 113.9 g (93% of theory) of the aldoxime.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N:9]1([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:15]3[CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:21])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Product: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
The title compound is prepared starting with 5-iodo-pyridin-2-ylamine and (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone following a procedure significantly analogous to Procedure FF. MS (m/e): 351.2 (M+1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:22])[CH3:21].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH:20]([OH:22])[CH3:21])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(O)c1ccncc1Br
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(O)c1ccncc1-c1ccc(C#N)c(F)c1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
To the solution of 4-cyano-3-fluoro phenylboronic acid (247 mg, 1.50 mmol), 1-(3-Bromo-pyridin-4-yl)-ethanol (303 mg, 1.50 mmol) and PdCl2(dppf). CH2Cl2 adduct (98 mg, 0.12 mmol) in DMF (6 mL) was added 2M Na2CO3aq (1.50 ml, 3.00 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (10% MeOH/DCM=0-25%) to give 2-Fluoro-4-[4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (190 mg, 52%) as colorless solid; ESI-MS m/z: 243 [M+1]+, Retention time 1.05 min
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncc2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cncc2c1CCNC2
Yield: 79.4 %

Procedure:
In a 2 L 3-necked flask equipped with a mechanical stirrer and condenser was placed 7-benzyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (11.28 g, 0.04) in methanol (500 mL). To this solution was added ammonium formate (37.8 g, 0.6 mol) and 10% Pd/C (11 g, 50% water wet). The resulting mixture was stirred and heated to reflux for 15 min. The reaction mixture was filtered through glass microfiber filter paper. The catalyst on filter paper was washed with hot methanol (200 mL). The filtrate was concentrated under reduced pressure to give a solid residue. The residue was purified by flash chromatography over silica gel (120 g) with anhydrous sodium sulfate (15 g) on top packed with hexane. The column was eluted with 100 mL portions of dichloromethane for fractions 1-4, 5% of (10% ammonia in methanol) in dichloromethane for fractions 6-9, and 10% of (10% ammonia in methanol) in dichloromethane for fractions 10-18. All fractions checked by TLC [10% of (10% ammonia in methanol) in dichloromethane]. The product was eluted in fractions 11-16 to give the title compound (6.1 g, 79%) as a light yellow solid. 1H NMR 60 MHz, (CDCl3), δ 8.8 (s, 1H), 8.2 (s, 1H), 4.0 (s, 2H), 3.8 (s, 3H), 3.0 (s, 4H), 1.7 (s, 1H).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[C:18]([Br:27])[CH:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Br:27][C:18]1[CH:17]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:28])[CH:21]=[C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cc(-c2nnn[nH]2)c1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,3S,5R)-3-[3-bromo-5-(1H-tetrazol-5-yl)-phenylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (200 mg, 0.445 mmol) in CH2Cl2 (2 mL) was added TFA (0.686 ml, 8.9 mmol). The reaction mixture was stirred at RT for 4 h. After completion the reaction mixture was diluted with CH2Cl2 and MeOH and the volatiles were removed under vacuum. MeOH was added and the reaction mixture concentrated again under vacuum. This operation was repeated twice to afford a mixture in a 2/3 ratio of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [3-bromo-5-(1H-tetrazol-5-yl)-phenyl]-amide: MS (LC/MS): 349.2 [M+H]+; tR (HPLC conditions k): 3.06 min and (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [3-bromo-5-(1-tert-butyl-1H-tetrazol-5-yl)-phenyl]-amide: MS (LC/MS): 405.3 [M+H]+; tR (HPLC conditions k): 4.46 min.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].[I-].[K+].ClCC1[N:11]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:22])[C:13]=2[N:23]=1.O.[OH-].[Li+]>O>[NH2:22][C:14]1[C:13]2[N:23]=[C:2]([CH2:1][OH:4])[N:11]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:12]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1CCOCC1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Product: Nc1nc2ccccc2c2c1nc(CO)n2CC1CCOCC1
Temperature: 50 °C
Reaction time: 17 h
Yield: 38.6 %

Procedure:
Potassium acetate (0.41 g, 4.16 mmol) and potassium iodide (0.28 g, 1.66 mmol) were added to a stirring solution of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.55 g, 1.66 mmol) and the resulting suspension was heated to 50° C. After 17 hours, the suspension was cooled to ambient temperature and concentrated under reduced pressure. The residue was suspended in methanol (10 mL) and water (5 mL) and lithium hydroxide monohydrate (0.35 g, 8.31 mmol) was added in one portion. The resulting solution was stirred at ambient temperature 18 hours and concentrated under reduced pressure. The residue was diluted with water (20 mL) and neutralized with hydrochloric acid (6 N in water). The aqueous layer was extracted with dichloromethane (2×50 mL) and ethyl acetate (50 mL). The combined organic fractions were concentrated to a yellow solid which was crystallized from acetonitrile. The crystals were isolated by filtration and dried in a vacuum oven at 65° C. to provide 0.20 g of [4-amino-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol as an off-white solid, mp 239-241° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2=[N:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]2[N:14]=1>CN(C)C=O>[CH3:9][C:5]1[N:4]=[C:3]([CH2:2][O:1][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3=[N:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:15]3[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reactant: Cc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(COc2nn3c(-c4ccccc4)nnc3c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxymethyl-6-methylpyridine (Example 67 part b, 0.5 g), in anhydrous dimethylformamide (20 ml) under nitrogen was added sodium hydride (107 mg of 60% in oil) and the reaction mixture was stirred at room temperature for 0.5 hours. To this mixture was added 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (Example 67 part d, 330 mg) and the solution was heated to 80° C. for 0.25 hours. After cooling the solvent was removed under vacuum, and the residue was dissolved in dichloromethane (30 ml) and washed with water and brine. After drying (MgSO4), the solution was filtered and evaporated to give the required product which was recrystallised from a mixture of ethyl acetate and hexane to give the title compound (210 mg, m.p. 186-187° C.). 1H NMR (360 MHz, DMSO) δ 2.52 (3H, s), 5.65 (2H, s), 7.25 (1H, d, J=7.7Hz), 7.49 (1H, d, J=7.7Hz), 7.58 (3H, m), 7.76 (1H, t, J=7.7Hz), 7.94 (1H, t, J=7.6Hz), 8.08 (1H, t, J=7.7Hz), 8.30 (3H, m), 8.58 (1H, d, J=7.6Hz); MS (ES+) m/e 368 [MH]+. Anal. Found C, 71.32; H, 4.44; N. 18.53. C22H17N5O. H2O requires C, 71.22; H, 4.73; N, 18.88%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13]1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1c1ccccc1
Temperature: -78 °C

Procedure:
To a flame dried flask equipped with stir bar was added 150 mL anhydrous dichloromethane which was cooled to −78° C. Oxalyl chloride (3.8 mL, 44 mmol) and DMSO (4.8 mL, 61 mmol) were added sequentially and the reaction stirred for 10 min. tert-butyl (2S,4S)-4hydroxy-2-phenylpyrrolidine-1-carboxylate (5-2, 2.28 g, 8.73 mmol) in 10 mL anhydrous dichloromethane was added dropwise and stirred 1 h at −78° C. Triethylamine (12 mL, 87mmol) was added and the reaction was warmed to 0 C over 1 h. Upon completion, the reaction was washed with 5% NaHCO3, brine and dried over MgSO4. The organic layer was concentrated to provide crude tert-butyl (2S)-4-oxo-2-phenylpyrrolidine-1-carboxylate (5-3). Recrystallization was effected with EtOAc/hexanes. 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 3H), 7.17 (m, 2H), 5.38 (m, 1H), 4.08 (d, J=19.5 Hz, 1H), 3.90 (d, J=19.3 Hz, 1H), 3.13 (dd, J=18.8, 9.8 Hz, 1H), 2.58 (dd, J=18.6, 2.4 Hz, 1H), 1.40 (br s, 9H); MS 206.0 found, 206.1 (M−C(CH3)3) required.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(O)C.C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 0.37 mmol) was dissolved in ethanol (4 ml) and a solution (4 ml) of 4N hydrogen chloride in ethyl acetate was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether (2 ml) and recrystallized from ethyl acetate-ethanol (20:1) to give 3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.12 g, 80%) as a colorless powder.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:17]2[C:18]=1[C:7](=[O:8])[CH:6]([CH3:11])[CH2:10]2
Reactant: CC(C)c1cccc(Br)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc(C(C)C)cc(Br)c2C1=O
Temperature: -10 °C

Procedure:
To a mixture of 34.9 g (0.26 mol) of AlCl3 and 350 ml of dichloromethane, a solution of 50.9 g (0.22 mol) of 2-bromo-2-methylpropanoyl bromide in 120 ml of dichloromethane was added dropwise with vigorous stirring at −10° C. Then, a solution of 40.0 g (0.20 mol) of 1-bromo-3-isopropylbenzene in 70 ml of dichloromethane was added dropwise at this temperature. The resulting mixture was refluxed for 12 h and then poured onto 2000 cm3 of ice. The organic product was extracted with 4×300 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 130-135° C./1.5 mm Hg. Yield 36.2 g (67%).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.CN(C)[CH:13]=[O:14].Cl>O1CCCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([F:9])[CH:8]=1)[CH:13]=[O:14]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A 28 g portion of magnesium turnings was suspended in 60 ml of tetrahydrofuran (THF) to which was subsequently added dropwise 800 ml of THF solution containing 200 g of 3,5-difluoro-1-bromobenzene at such a rate that the solvent was gently refluxed. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and then 91 g of N,N-dimethylformamide (DMF) was added dropwise thereto. After the dropwise addition, this was further stirred at room temperature for 1 hour, mixed with 1,000 ml of 10% hydrochloric acid and again stirred for 1 hour. This was extracted with 1,000 ml of ethyl acetate, washed twice with saturated brine and then dried with anhydrous sodium sulfate. By evaporating the solvent, 125 g of 3,5-difluorobenzaldehyde was obtained.