Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].Cl.[CH:19]([NH:22][NH2:23])([CH3:21])[CH3:20].C(N(CC)CC)C>C(O)C>[NH2:6][C:5]1[N:22]([CH:19]([CH3:21])[CH3:20])[N:23]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: CC(C)NN
Reactant: COC(=C(C#N)C#N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C#N)c1N
Yield: 78.6 %

Procedure:
Compound 25 (5 g, 21.8 mmol), isopropylhydrazine hydrochloride (2.41 g, 21.8 mmol) (purchased from Ryan Scientific) and triethylamine (6.40 mL, 46.0 mmol) were allowed to react in ethanol (145 mL) at room temperature for 1 hr. After concentrating the reaction mixture, it was purified by silica chromatography using a chloroform/methanol solvent system (methanol gradient increased with time from 0-10%). The relevant fractions were concentrated in vacuo to yield a yellow powder (4.65 g, 79% yield): 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.24 (m, 2H), 7.78 (t, J=8.2, 1H), 6.82 (br, 2H), 4.53 (hept, J =6.5, 1H), 1.36 (d, J=6.5, 6H). 13C NMR (100 MHz, DMSO) δ 153.04, 148.76, 146.98, 133.97, 132.22, 131.19, 123.80, 120.37, 116.28, 70.74, 48.64, 22.02; [M+H]+ calculated for C13H11N5O2 272.1, found 272.3.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH2:64])[CH:61]([CH3:63])[CH3:62]>CN(C=O)C>[CH2:60]([NH:64][C:24]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:15]=1[NH:14][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:13])[NH:21][CH:20]=[CH:19]2)=[O:25])[CH:61]([CH3:63])[CH3:62]
Reactant: CC(C)CN
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 μL, 0.2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, 66%). 1H-NMR (400 MHz, DMSO-d6) δ 12.66 (d, J=7.4 Hz, 1H), 12.42 (s, 1H), 11.21 (s, 1H), 8.81 (d, J=6.6 Hz, 1H), 8.47 (s, 1H), 8.36 (t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.72-7.71 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (m, 1H), 6.48 (m, 1H), 3.10 (t, J=6.2 Hz, 2H), 1.88 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); HPLC ret. time 2.73 min, 10-99% CH3CN, 5 min run; ESI-MS 403.3 m/z (MH+).
Reaction SMILES: C([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1)(=O)C.[OH-].[K+].Cl>C(O)C>[NH2:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:16][CH3:17])[CH:6]=1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)O

Procedure:
Methyl 4-acetamido-5-chloro-2-methoxybenzoate is dissolved in ethanol and aqueous potassium hydroxide added. The solution is refluxed for a short time, cooled and concentrated hydrochloric acid added. The resulting precipitate is filtered off, washed with water and dried to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1F
Reactant: Brc1ccccn1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(F)cc1F
Yield: 60.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt: 70/30 as eluent) to afford 193 mg of tert-butyl 2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a brown oil (Yield: 61%).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]>CN(CN(C)C)C>[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:1])[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (100 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g., 0.01 mole) in bis(dimethylamino)methane (100 ml.) under nitrogen with cooling to maintain the reaction mixture temperature below 60° C. The reaction mixture is stirred at 25° C. for 2 hours, and poured into ice water (1500 ml.) to precipitate 7.4 g. of 2,3-dichloro-4-(2-phenylacryloyl)anisole which melts at 87°-89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:26]1[CH:27]=[C:28]2[C:23]([CH:22]=[CH:21][NH:20]2)=[CH:24][CH:25]=1)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1H-indole-6-carboxylic acid. MS: 403.3 (M+H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](I)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:21]1[CH:26]=[C:25]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:24]=[N:23][CH:22]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Brc1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A flask containing 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (2 g, 7.66 mmol), 3-bromo-5-iodopyridine (1.45 g, 5.11 mmol), 2M K2CO3 in water (5.11 mL, 10.21 mmol), PS—Pd(PPh3)4 (2.84 g, 0.255 mmol) is flushed with N2 and dioxane (50 mL) is added. The mixture is stirred at 60° C. for 3 h, whereupon another portion of 3-bromo-5-iodopyridine (300 mg, 1.06 mmol) is added. The mixture is stirred at 60° C. overnight. The mixture is cooled to room temperature and silica gel (20 g) is added. The suspension is concentrated in vacuo and the residue is placed under high vacuum at 60° C. over the weekend. The mixture is purified by silica chromatography eluting with a 1:9 to 7:3 EtOAc-heptane gradient to give 2-(5-bromopyridin-3-yl)-1H-indole. MS (ESI) m/z 273.0, 275.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[C:10]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:18][CH2:19]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCN1CCC(=O)CC1
Product: CCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Yield: 71 %

Procedure:
Prepared analogously to Example A19a) from 1-ethyl-4-piperidinone and 1-(phenylmethyl)piperazine in a yield of 71% of theory. Colourless, amorphous substance, Rf=0.46 (FM4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]([CH2:18]Cl)=[CH2:17]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([Cl:15])=[CH2:17])=[CH:4][CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc(Cl)cc1
Yield: 92.5 %

Procedure:
To a mixture of 4-chlorophenol (6.1 g, 47.4 mmol) and potassium carbonate (13.1 g, 94.7 mmol) in acetone (200 mL), 2,3-dichloropropene (6.6 mL, 71 mmol) was added. After heating to reflux the reaction mixture for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with more acetone and the combined filtrates were concentrated in vacuo. The crude pale brown liquid (11.5 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 85/15) to give 1-(4-chlorophenoxy)-2-chloro-2-propene (8.9 g, 98%) as a white liquid: Anal. Calc'd. for C9H8OCl2: C, 53.23, H, 3.97. Found: C, 53.09, H, 3.95.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:10]2[CH:18]=[CH:17][N:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1>>[C:2]1([NH:1][C:13]2[N:14]=[CH:9][C:10]3[CH:18]=[CH:17][N:16]=[CH:15][C:11]=3[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2cnccc12
Product: c1ccc(Nc2ncc3ccncc3n2)cc1
Yield: 22 %

Procedure:
Using a procedure analogous to that described in Example 5, this product was prepared in 22% yield from aniline (1.8 eq.) and 4-chloropyrido[3,4-d]pyrimidine (1 eq.). MP 161° C.; LC-MS: 223 (MH+).
Reaction SMILES: [N:1]1([C:5]2[O:6][C@H:7]3[CH2:13][C@H:12]([CH2:14][F:15])[C@@H:11]([O:16]CC4C=CC=CC=4)[C@H:10]([O:24]CC4C=CC=CC=4)[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[N:1]1([C:5]2[O:6][C@H:7]3[CH2:13][C@H:12]([CH2:14][F:15])[C@@H:11]([OH:16])[C@H:10]([OH:24])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC[C@H]1C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O[C@@H]1[C@@H](CF)C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@H]1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-2-(azetidin-1-yl)-4,5-bis(benzyloxy)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (80.0 mg, 0.189 mmol) in DCM (2 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 0.47 mL, 0.47 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 5 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (5 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 3%-8% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(azetidin-1-yl)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (36.5 mg, 79%) as a white solid. MS m/z 267.2 (M+23, 100%); 1H NMR (400 MHz, MeOD) δ 4.61-4.69 (m, 1.5H), 4.53-4.57 (m, 1H), 4.43 (dd, J=9.0 Hz, 2.8 Hz, 1H), 4.00 (t, J=7.6 Hz, 1H), 3.58 (t, J=7.2 Hz, 1H), 3.15-3.28 (m, 2H), 2.22-2.36 (m, 3H), 1.75-1.87 (m, 2H); 13C NMR (100 MHz, MeOD) δ 164.81, 85.13 (d, J=160.7 Hz), 81.98, 80.60 (d, J=0.6 Hz), 71.88 (d, J=4.8 Hz), 69.03, 39.37 (d, J=18.6 Hz), 28.09 (d, J=3.9 Hz), 17.75.
Reaction SMILES: [CH3:1][Cl:2].B(F)(F)F.[CH3:7][C:8](=[CH2:10])[CH3:9]>>[CH3:9][C:8](=[CH2:7])[CH3:10].[CH2:1]([Cl:2])[C:8](=[CH2:7])[CH3:9]
Reactant: CCl
Agent: C=C(C)C
Agent: FB(F)F
Product: C=C(C)CCl

Procedure:
About 10 parts by weight of fine, granular, hydrated silica and 20 parts by weight of methallyl chloride are mixed then agitated at ambient temperature for about 1 hour, thereby producing as mixture of poly (methyallyl chloride) polymer, methallyl chloride and hydrated silica. About 50 parts by weight of methyl chloride, containing a Friedel-Crafts catalyst, boron trifluoride, in the amount of 0.8 parts by weight, are added to said mixture and cooled to -40 degree to -100 degree F.; then this mixture is slowly added to a mixture containing about 100 parts by weight of isobutylene and 150 parts by weight of methyl chloride while agitating and keeping the temperature between -40 degree to -100 degree F., thereby producing poly (methallyl chloride isobutylene) copolymer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[N:20][CH:21]=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[N:20][CH:21]=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3cnccc32)cc1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2cnccc21

Procedure:
By the same method as in Example 3, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone (60 mg, 0.140 mmol) and 1M solution of boron tribromide (0.84 ml, 0.840 mmol) were reacted, and then the reaction mixture was neutralized (pH=7) by using saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain solid. The obtained solid was recrystallized from dichloromethane and n-hexane to obtain the target compound 6, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone, as white solid (28 mg, 48%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Cl)[C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1.[CH3:41][N:42](C)C=O>[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1)[C:41]#[N:42]
Reactant: CN(C)C=O
Reactant: Clc1cncc(Cl)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cncc(Cl)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 175 °C
Yield: 13 %

Procedure:
2-(3,5-Dichloropyridin-4-yl)-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine bis(trifluoroacetate) (200 mg, 0.3 mmol), zinc cyanide (231 mg, 1.97 mmol), and tetrakis-(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) were stirred in N,N-dimethylformamide and degassed for 10 minutes by bubbling with nitrogen gas. The mixture was heated in a microwave for 20 minutes at 175° C. Purification by preparative LCMS gave the desired product (25 mg, 13%). 1H NMR (DMSO-d6): δ 9.20 (d, 2H), 8.60 (m, 1H), 8.0 (m, 1H), 7.65 (m, 1H), 6.90 (m, 1H). LC/MS: 372 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([CH3:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([CH3:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Yield: 50.1 %

Procedure:
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (0.4 g, 0.9 mmol) (prepared in Example C52, step C) and 2,4-dichloro-5-methylpyrimidine (0.152 g, 0.936 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product (0.25 g, 39%). LCMS for C29H37ClN5O4 (M+H)+: m/z=554.2.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1COCC1.[Cl-].[Na+].O>[C:9]([C:11]1([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a stirred solution of lithium diisopropylamide (2M solution in THF; 60 ml; 0.12 mol) in THF (60 ml) at −70° C. was added tert-butyl 4-cyanopiperidine-1-carboxylate (21 g; 0.1 mol) in THF (150 ml) over 1 hour. The mixture was stirred at −70° C. for 1 hour and then (bromomethyl)cyclopropane (17.53 g; 0.13 mol) in THF (20 ml) was added. The solution was stirred at −70° C. for 1 hour then allowed to warm to ambient temperature over 2 hours. The reaction was poured into brine (150 ml) and extracted with EtOAc (3×200 ml). The combined organic extracts were washed with brine (200 ml), dried over MgSO4, filtered and evaporated to give a brown oil. The crude product was chromatographed on silica eluted with 5% EtOAc in isohexane to give the title product as a colourless oil. (24.8 g)
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:26])[C:9]2[CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:12]=[N:13][C:14]=2[CH:15]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[CH2:27]([O:26][C:8]1[CH:7]=[C:6]([CH3:5])[CH:15]=[C:14]2[C:9]=1[CH:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[N:12]=[N:13]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Temperature: 25 °C
Yield: 10 %

Procedure:
To an acetone solution (5 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (69 mg, 0.2 mmol) obtained in Example 70 were added benzyl bromide (0.024 mL) and potassium carbonate (28 mg, 0.2 mmol), followed by stirring at room temperature over night and refluxing under heating for 3 hours. The reaction liquid was further added with benzyl bromide (0.024 mL) and potassium carbonate (28 mg, 0.2 mmol), followed by stirring at room temperature over night, concentration of the reaction liquid under reduced pressure, adding distilled water (1 mL), extraction with ethyl acetate and purification of residue obtained after concentration of an organic layer under reduced pressure, with HPLC column chromatography (hexane/ethyl acetate=3/1) to obtain an objective compound (8 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:14][C@@H:15]([CH2:23][CH2:24][CH3:25])[CH:16]([CH2:19][C:20](=O)[CH3:21])[CH:17]=O.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]1[CH:14]=[C:15]([C@@H:16]([CH3:17])[CH2:19][CH2:20][CH3:21])[CH:23]=[C:24]1[CH3:25])=[O:5]
Reactant: CCC[C@H](C)C(C=O)CC(C)=O
Reactant: CSc1ccc(C(=O)NN)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](C)c1cc(C)n(NC(=O)c2ccc(SC)cc2Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
The compound prepared in Example 76 (1.65 g) and (3S)-3-methyl-2-(2-oxopropyl)hexanal (1.86 g) were dissolved with tetrahydrofuran (10 mL), and 5N hydrochloric acid (0.2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed by water and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=85/15→65/35) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](Cl)=[O:38]>>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)CC(F)(F)F
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)CC(F)(F)F)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and 3,3,3-trifluoropropionyl chloride.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([O:22][C:23]2[C:24]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][C:19]([N:35]=[C:36]=[O:37])=[C:18]([F:38])[CH:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([F:38])[C:19]([N:35]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:36]2=[O:37])=[CH:20][C:21]=1[O:22][C:23]1[C:24]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)COc1ncccc1Oc1cc(N=C=O)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To a mixture of 1 ml of N,N-dimethylformamide and 26 mg of sodium hydride, a solution of 126 mg of ethyl 3-amino-4,4,4-trifluorocrotonate in 1 ml of N,N-dimethylformamide was added and the mixture was stirred at 0° C. Thereafter, to the reaction mixture was added a mixture of 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl isocyanate and 1 ml of N,N-dimethylformamide at the same temperature, and the mixture was stirred over night at room temperature. The reaction solution was poured into a mixture of hydrochloric acid and ice water, and to obtain 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.