Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].N([O-])=[O:12].[Na+].O>Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([OH:12])[N:9]=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: N#Cc1c(Cl)ccnc1N
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: N#Cc1c(Cl)ccnc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution 2-amino-4-chloronicotinonitrile (90 mg, 0.59 mmol), NaNO2 (45 mg, 0.65 mmol), in HCl (6M, 1 mL) was added CuSO4 (94 mg, 0.59 mmol). The resulting mixture was allowed to stir at 0° C. for 0.5 h. To the solution was added water (2 ml), extracted with EtOAc (2×5 mL), dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid. LC/MS m/z=155.2 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[NH:9][C@@:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5]2.[CH:16]1([O:19][C:20]2[CH:27]=[CH:26][C:25]([N:28]3[C:32]([C:33]([F:36])([F:35])[F:34])=[N:31][N:30]=[N:29]3)=[CH:24][C:21]=2[CH:22]=O)[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C(OCC)(=O)C.C(O)(=O)C>[CH:16]1([O:19][C:20]2[CH:27]=[CH:26][C:25]([N:28]3[C:32]([C:33]([F:34])([F:35])[F:36])=[N:31][N:30]=[N:29]3)=[CH:24][C:21]=2[CH2:22][NH:1][C@@H:2]2[CH2:8][CH2:7][C@@H:6]3[NH:9][C@@:3]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]3)[CH2:18][CH2:17]1
Reactant: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1OC1CC1
Reactant: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: FC(F)(F)c1nnnn1-c1ccc(OC2CC2)c(CN[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
(1R*,2R*,5S*)-2-Amino-1-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 50 mg, 0.25 mmol) and 2-(cyclopropoxy)-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (119 mg, 0.4 mmol) [See International (PCT) Patent Publication No. WO 99/24423, published 20 May 1999] were dissolved in 1,2-dichloroethane (5 mL) and treated with acetic acid (23 μL), followed by sodium triacetoxyborohydride (85 mg). The solution was stirred at ambient temperature for 16 hours, then quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL). The mixture was extracted with dichloromethane (2×50 mL) and the extracts were dried (MgSO4), then concentrated. The residue was purified by silica chromatography to give the free base, which was taken up in ethyl acetate (10 mL) and treated with ethereal hydrogen chloride (1M, 2 mL). The solid formed was removed by filtration and recrystallized from methanol/ethyl acetate to give the title compound as a white solid (84 mg, 0.15 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15](O)=[O:16])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(Cl)(=O)C(Cl)=O.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:46])[CH:33]([NH2:45])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([OH:46])[CH:33]([NH:45][C:15]([C:10]2[C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2](=[O:1])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[CH:30][CH:31]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2c1-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 9-oxo-9H-fluorene-4-carboxylic acid (144 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (154 mg, 69%).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.49 mL (3.5 mmol) of triethylamine was added and dissolved in a suspension of 0.56 g (3.2 mmol) of ascorbic acid in acetonitrile (7 mL). After the above crude product of (4,8,12,16-tetramethylheptadec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1>C(O)(=O)C>[NH:4]1[CH:5]=[CH:6][C:2]([N:1]2[C:7](=[O:8])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:16])=[N:3]1
Reactant: Nc1cc[nH]n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 130 °C

Procedure:
1.2 3-Amino-pyrazole (278 mmol) is dissolved in acetic acid (240 ml) and isobenzofurane-1,3-dione (1 eq.) is added. The reaction solution is heated to 130° C. for 14 h. After cooling to RT, the precipitate is filtrated and washed with ethylacetate/heptane (1:1). 2-(1H-Pyrazol-3-yl)-isoindole-1,3-dione is obtained as a colourless powder; HPLC (Method B): 2.69 min; LC-MS (Method B): 1.360 min, 214.15 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1>CO.[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 66.1 %

Procedure:
13.5 g ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate, dissolved in 110 ml methanol and 39 ml 2 N aqueous potassium hydroxide solution, are maintained at reflux temperature for 12 hours. The solution is then evaporated in a vacuum. After dilution with water, it is extracted with diethyl ether, the aqueous phase is filtered, with the addition of active charcoal, and the filtrate is acidified. There are obtained 11.7 g (95% of theory) of acid which is recrystallized from 25 ml glacial acetic acid. There are obtained 8.2 g (66% of theory) 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetic acid; m.p. 186°-187° C. From the mother liquor, there is obtained a further 1.9 g (15% of theory) of this acid, which has a melting point of 182°-183° C.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[F:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: FC1(c2ccc(Br)cc2)CCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2(F)CCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 1.64 g of 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (7.16 mmol), 4.92 ml of a 1.6 molar solution of n-BuLi in hexane (7.87 mmol) and 1.1 ml of DMF (14.32 mmol). 4-(1-Fluoro-cyclobutyl)-benzaldehyde was isolated crude as a light yellow liquid (1.23 g, 96%). 1H NMR (CDCl3, 300 MHz): δ 1.84 (m, 1H), 2.15 (m, 1H), 2.49-2.81 (m, 5H), 7.63 (d, J=8 Hz, 2H), 7.92 (d, J=8 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(diethyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C7) (2.25 g, 6.54 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (1.55 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>CN(C=O)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15]([Cl:35])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC=C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCC=C(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.7 g (5 mmol) of 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenoic acid, 20 ml of toluene and 73 μl of DMF were introduced into a round-bottomed flask. The mixture was heated to 50° C. and 714 μl (6 mmol) of thionyl chloride were added and the mixture was stirred at this temperature for one hour. The mixture was evaporated to dryness and the crude acid chloride was employed as is in the synthesis to follow.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[F:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:38][CH:35]3[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][F:29])[CH2:33][CH2:34]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: NC1CCN(CCF)CC1
Product: COc1ccc(Cn2nc(NC3CCN(CCF)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (245 mg, 0.500 mmol, prepared according to Example 7, Step B) and 1-(2-fluoroethyl)piperidin-4-amine (219 mg, 1.50 mmol) according to the procedure described for Example 138, Step C. Yield: 128 mg (50%). LRMS (APCI+): 100% purity, 220 nm, m/z 509 (M+1) detected.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][C:17]1[C:22]([CH:23]2[N:28]3[C:29](=[O:42])[NH:30][C:31]4=[CH:32][CH:33]=[C:34]([C:35]5[C:36]([CH3:41])=[N:37][O:38][C:39]=5[CH3:40])[C:26](=[C:27]34)[O:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>C(Cl)Cl>[CH3:41][C:36]1[C:35]([C:34]2[C:26]3[O:25][CH2:24][CH:23]([C:22]4[C:17]([CH2:16][NH:15][C:3](=[O:4])[CH3:2])=[N:18][CH:19]=[CH:20][CH:21]=4)[N:28]4[C:29](=[O:42])[NH:30][C:31]([C:27]=34)=[CH:32][CH:33]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1CN
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1ncccc1C1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Yield: 74 %

Procedure:
A solution of 4-[2-(aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one bis(trifluoroacetate) (35.0 mg, 0.058 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (50.3 μL, 0.289 mmol) and stirred. Once the starting material was completely dissolved, the reaction mixture was treated with acetyl chloride (49.3 μL, 0.069 mmol) (added as a 10% solution in dichloromethane) and stirred at room temperature for 1 h. The reaction mixture was quenched with methanol and the solvent was concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (18 mg, 74%) as a racemic mixture. 1H NMR (500 MHz, DMSO-d6) δ 10.98 (br s, 1H), 8.50-8.47 (m, 1H), 8.44 (dd, J=5.2, 5.2 Hz, 1H), 7.26 (dd, J=7.9, 4.7 Hz, 1H), 7.23-7.16 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.68 (dd, J=3.1, 3.1 Hz, 1H), 4.71 (dd, J=15.1, 6.1 Hz, 1H), 4.55-4.47 (m, 2H), 4.44 (dd, J=11.6, 3.2 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.88 (s, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 68.8 %

Procedure:
1.5 g (6.5 millimoles) of 2-(m-nitrophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 32b), dissolved in 80 ml of tetrahydrofuran, are hydrogenated with 0.5 g of 10% strength palladium on charcoal at room temperature. When the hydrogen absorption has ceased, the catalyst is filtered off and the filtrate is concentrated. The residue is recrystallized from an ethyl acetate/methanol mixture. 0.9 g (69% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one is obtained as colorless crystals, which are identical with the compound from Example 33.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.O[Li].O.Cl>CO.O>[C:20]([O:19][C:17]([NH:16][CH2:15][C:13]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:11][N:10]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=[C:9]2[CH:14]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)cn12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc2ncc(C(=O)O)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.3 %

Procedure:
To a suspension of 7-(tert-butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (1.39 g, 2.99 mmol) in MeOH (24 mL) and water (12 mL) was added LiOH.H2O (377 mg, 8.98 mmol) in one portion. The slurry was stirred at RT for 14 h then the clear solution was acidified to pH 5 by the addition of 2.0 M HCl in water. The resulting precipitate was filtered, the solid washed with water and dried under vacuum to yield the title compound (1.25 g, 2.76 mmol, 92%) as a colorless solid, which was used in the next step without further purification. MS: 436 [M+1]+; HPLC: AtRet=1.76.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:25])(=O)=O.C(OCC)(=O)C.CO>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:5]1[N:6]([CH3:25])[N:7]([CH2:17][CH:18]2[CH2:19][CH2:20]2)/[C:8](=[N:10]/[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C(F)(F)F)n(CC2CC2)n1
Reactant: COS(=O)(=O)OC
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A mixture of Example 1D (11.6 g, 40 mmol) and dimethyl sulfate (20.2 g, 160 mmol) in toluene (10 mL) was heated at 80° C. for 24 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 15-100% hexane in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (8.7 g, 72% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.41-0.53 (m, 4 H), 1.15-1.27 (m, 1 H), 1.38 (s, 9 H), 3.98 (s, 3 H), 4.20 (d, J=7.12 Hz, 2 H), 6.70 (s, 1 H); MS (ESI) m/z 304 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:3][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1
Reactant: Cc1ccccc1CN(C)CC(O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc2c1CN(C)CC2c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 62 %

Procedure:
The product from Step A (1.25 g, 4.1 mmol) was dissolved in trifluoroacetic acid (TFA, 7.5 mL), then trifluoroacetic anhydride (TFAA, 7.5 mL) was added. After stirring for 24 h, the solvents were removed in vacuo, the residue was dissolved in MeOH, and the solvent was removed in vacuo. The residue was dissolved in aqueous NH4OH, then extracted twice with CH2Cl2. The extract was dried over Na2SO4, filtered, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (40 g) eluting with 5% to 30% EtOAc/hexanes with 1% Et3N to give 2,8-dimethyl-4-naphthalen-2-yl-1,2,3,4-tetrahydroisoquinoline (0.73 g, 61%) as a clear, dark yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.88 (m, 4H), 7.38-7.48 (m, 2H), 7.26 (dd, J=8.3, 1.6 Hz, 1H), 6.93-7.04 (m, 2H), 6.74 (d, J=7.2 Hz, 1H), 4.45 (t, J=6.9 Hz, 1H), 3.75 (d, J=15.4 Hz, 1H), 3.51 (d, J=15.4 Hz, 1H), 3.06 (ddd, J=11.2, 5.6, 0.9 Hz, 1H), 2.67 (ddd, J=11.4, 8.5 Hz, 1H), 2.48 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([NH:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31])[CH2:26][CH2:27][CH3:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CCCCNC(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCCNC(=O)c1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 51.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(butylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro-[chroman-4,4′-imidazole]-6-yl)-N-butylbenzamide (12.4 mg, 50%). cis (2.50 mg, 10%). 1H-NMR (MeOD): 0.95 (m, 3H), 1.42 (m, 2H), 1.60 (m, 2H), 2.14 (d, 1H), 2.31 (t, 1H), 3.33 (s, 3H), 3.36 (d, 2H), 5.88 (d, 1H), 7.04 (d, 1H), 7.24 (s, 1H), 7.37 (m, 1H), 7.41 (t, 2H), 7.48 (d, 3H), 7.53 (d, 1H), 7.66 (d, 1H), 7.69 (d, 1H), 7.94 (s, 1H). trans (9.91 mg, 40%). 1H-NMR (MeOD): 0.96 (t, 3H), 1.43 (m, 2H), 1.61 (m, 2H), 2.03 (d, 1H), 2.52 (t, 1H), 3.33 (s, 3H), 3.39 (d, 2H), 5.30 (d, 1H), 7.05 (d, 1H), 7.25 (s, 1H), 7.39 (m, 1H), 7.42 (t, 2H), 7.47 (d, 3H), 7.53 (d, 1H), 7.67 (d, 1H), 7.70 (d, 1H), 7.93 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])[CH2:2][CH2:3][CH3:4].[S:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1>>[CH2:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][CH2:17][C:16]1[S:12][CH:13]=[N:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1cncs1
Reactant: CCCCc1ccccc1N
Product: CCCCc1ccccc1NCc1cncs1

Procedure:
The desired compound was prepared according to the method of Example 403H starting with 2-butylaniline and the aldehyde from Example 1202A. m/e (DCI) 247 (MH+)
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:23])([F:22])[CH:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)[O:12][CH3:13]>C(O)C>[F:23][C:10]([F:9])([F:22])[CH:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:21])=[O:2])[CH:15]=1)[O:12][CH3:13]
Reactant: O=C([O-])O
Reactant: COC(c1ccnc(C#N)c1)C(F)(F)F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: COC(c1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To 2 ml of ethanol were added 0.12 g of sodium bicarbonate and 0.1 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.2 g of 4-(2,2,2-thfluoro-1-methoxyethyl)pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 3 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(2,2,2-trifluoro-1-methoxyethyl)pyridine-2-carboxamide=oxime.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH3:15])=[CH:9][C:8]=1[F:31])(C)(C)C.C(OCC)C>C(O)=O>[CH2:24]([O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([F:31])[CH:9]=1)[CH2:14][CH3:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(F)c1
Solvent: CCOCC
Solvent: O=CO
Product: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)c(F)c1

Procedure:
tert-Butyl-4-[N-(2-benzyloxybenzyl)-N-ethylamino]-2-fluorobenzoate (1.81 g) in formic acid (5 mL) was heated on a steam bath until a clear solution was obtained. The reaction mixture was evaporated to dryness and the oil obtained solidified on trituration with diethyl ether to give 4-[N-(2-benzyloxybenzyl)-N-ethylamino]-2-fluorobenzoic acid, yield 0.51 g, mp 154° C.