Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9](N(C2CC2)C(C2C=NC(N3C=CN=C3CC)=NC=2)=O)[CH2:8][CH2:7]1)#[N:5].C(N(C(C)C)C(C)C)C>C(O)C>[OH:3][NH:2][C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[NH:5]
Reactant: NO
Reactant: CCc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(C#N)CC2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N=C(NO)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydroxylamine hydrochloride (36 mg) is added to 2-(2-ethyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (180 mg, Intermediate 32) and ethyldiisopropylamine (0.1 mL) in ethanol (30 mL) and the mixture is refluxed for 4 h. Another 10 mg hydroxylamine hydrochloride is added and the mixture is refluxed for 1 h and stirred at room temperature for 12 h. The solvent is removed in vacuo to yield the respective (N-hydroxycarbamimidoyl)-piperidine derivative as an intermediate. Subsequently 50 mg of the aforementioned intermediate are added to tetrahydrofuran (10 mL) followed by ethyldiisopropylamine (32 μL) and cyclopropanecarbonyl chloride (11 μL). The mixture is stirred at room temperature for 1.5 h. Acetonitrile is added and the mixture is refluxed for 5 h. The mixture is concentrated and 1,2-dicholorethane (2.0 mL) and (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent, 75 mg) are added and the mixture is heated in a microwave oven to 130° C. for 15 min. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/TFA) to yield the desired product. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [N+]([O-])(O)=O.C([NH:8][C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])(=O)C.Cl>>[NH2:8][C:9]1[CH:10]=[C:11]([C:18]2[CH:19]=[C:20]([CH3:25])[N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1cc(-c2cc(C)nc(C)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O=[N+]([O-])O
Product: Cc1cc(-c2ccc([N+](=O)[O-])c(N)c2)cc(C)n1

Procedure:
4-(3-Amino-4-nitrophenyl)-2,6-dimethylpyridine was prepared in two steps by first nitrating (with 45 ml. of concentrated nitric acid) 10 g. of 3-(2,6-dimethyl-4-pyridinyl)acetanilide using the procedure given above in the second paragraph of Example A-3 to produce 5.2 g. of 4-(3-acetylamino-4-nitrophenyl)-2,6-dimethylpyridine and hydrolyzing the latter compound (41.2 g.) with 6 N aqueous hydrochloric acid to produce 4-(3-amino-4-nitrophenyl)-2,6-dimethylpyridine (34.2 g.), m.p. 226°-229° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[C:44]([O:45][CH3:46])=[CH:43][C:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:35][CH2:36][C:30]=2[CH:29]=1>>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[N:7][C:2]([NH:27][C:28]2[C:44]([O:45][CH3:46])=[CH:43][C:31]3[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:35][CH2:36][C:30]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3-n3cccn3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-2-pyrazol-1-yl-phenyl)-amine was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product 2-{7-[5-Chloro-4-(4-morpholin-4-yl-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.90 (m, 2H), 8.20 (m, 2H), 7.80 (m, 2H), 7.68 (s, 1H), 7.14 (s, 1H), 7.01 (m, 1H), 6.92 (s, 1H), 6.50 (s, 1H), 4.33 (s, 2H), 3.79 (m, 7H), 3.58 (bm, 2H), 3.35-3.15 (m, 5H), 3.15-3.07 (m, 4H), 2.99 (s, 6H), 2.50 (m, 1H); MS (m/e) 632.51 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:24])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1c(Br)ccc2c1CCC(=O)N2
Solvent: Cc1ccccc1
Product: N#Cc1c(Br)ccc2c1CCC(=S)N2
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-2; 1.3 g, 0.0052 mol) in toluene (20 mL) was added Lawesson's reagent (2.1 g, 0.0052 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, DMSO-d6) δ 7.612-7.561 (m, 1H), 6.980-6.959 (t, J=8.4 Hz, 1H), 3.779-3.769 (d, J=4 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[CH3:25]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[C:16]([CH3:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1sc2c(c1C)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1sc2c(c1C)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2
Yield: 64 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3,4-Trimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccccc2Cl)CC1
Yield: 12 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-chloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (8.2 mg, 12%) as light yellow oil. MS m/e=525.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:19].[OH:20]C1C=C(C=CC=1)C=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[CH:13]=1)[CH2:6][C:5]2=[O:19]
Reactant: O=C1CC(c2ccc(F)cc2)Oc2ccc(O)cc21
Reactant: O=Cc1cccc(O)c1
Product: O=C1CC(c2cccc(O)c2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one was prepared as described for 6-hydroxy-2-(4-fluorophenyl)chroman-4-one in Example 2(a) but starting from 3-hydroxybenzaldehyde. The product was recrystallised from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, 1H), 9.41 (bs, 1H), 7.22-7.17 (m, 1H), 7.11 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H J 3.0, 8.9 Hz), 6.64 (d, 1H, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-6.73 (m, 1H), 5.46 (dd, 1H J 2.9, 12.7 Hz), 3.09 (dd, 1H, J 12.7, 16.9 Hz), 2.75 (dd, 1H, J 2.9, 16.9 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][C:5]=1[CH2:15][CH:16]=[CH2:17].C(S)CC.CC(C)([O-])C.[K+].BrC[C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:30]([O:32][CH3:33])=[O:31])[C:7]=2[O:6][C:5]=1[CH:15]=[CH:16][CH3:17]
Reactant: C=CCc1oc2c(OC)cccc2c1CCO
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: CCCS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=Cc1oc2c(OCC(=O)OC)cccc2c1CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
3-(2-hydroxyethyl)-7-methoxy-2-(2-propenyl)benzofuran (1.43 g), n-propanethiol (0.84 ml) and potassium t-butoxide (968 mg) were dissolved in DMF (15 ml) and the solution was stirred at room temperature for 5 minutes and then at 100° C. for 5 hours. After cooling the reaction temperature to room temperature, methyl bromoacetate (0.87 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (630 mg, yield: 35%).
Reaction SMILES: [N+:1]([C:4]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])([O-:3])=[O:2].[OH-].[K+]>C(O)C>[N+:1]([C:4]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Reaction time: 1.7 h

Procedure:
Ethyl 2-nitro-3-(2-chlorophenoxy)benzoate was suspended in 1N-potassium hydroxide (60 ml) and ethanol (60 ml) and stirred for 1.7 hrs. Ethanol was distilled off from the reaction mixture, and the remaining aqueous solution was washed with diethyl ether and acidified at 0° C. The precipitating crystals were collected by filtration, washed with water and dried over phosphorus pentoxide in vacuo to give 2-nitro-3-(2-chlorophenoxy)benzoic acid (11.3 g). mp 185°-187° C.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:5][CH:6]2[CH2:9][N:8]([C:10]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=3[C:12]([OH:14])=[O:13])[CH2:7]2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(Cl)cc2)C1
Yield: 130 %

Procedure:
The title compound (D123) (125 mg) was prepared according to the experimental procedure described in Description 103A vero starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 4-Chlorophenol (0.033 ml, 0.338 mmol).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].Cl>O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(N)CCC(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A stirred solution containing 4-amino-4-methylpentanoic acid (0.90 g, 6.86 mmol, Chembridge), Na2CO3 (2.9 g, 27. mmol), and 1,4-dioxane (10 mL) was cooled in an ice bath and Fmoc-Cl (2.1 mg, 8.2 mmol) dissolved in 1,4-dioxane (10 mL) was added in over about 2 min. The mixture was stirred at about 0° C. for about 1 h and then allowed to warm to rt. The mixture was neutralized with aqueous 6 N HCl and extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatograph (40 g silica gel column, 10-60% EtOAc/Heptane) to give 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-methylpentanoic acid the title compound (1.2 g, 49%): LC/MS (Table 2, Method b) Rt=2.31 min.; MS m/z: 352 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 58.1 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (805 mg, 3.0 mmol) and 4-cyano-benzohydrazide (483 mg, 3.0 mmol) were coupled in a procedure analogous to that used for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (10 mL) followed by cooling to 0° C. and filtration to yield product as a light yellow solid (718 mg, 50%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.85 (br s, 2H), 8.09 (AA′XX′, J=8.2 Hz, 2H), 7.92 (AA′XX′, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.27 (m, 1H), 4.16 (dd, J=5.0, 7.3 Hz, 1H), 2.88 (br s, 1H), 2.34 (s, 3H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O>[Pd].CO>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)cc1N
Yield: 99.9 %

Procedure:
A mixture comprising 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 mL) in a Parr apparatus was hydrogenated at 50 psi for 3 hours, filtered through celite and concentrated in vacuo to provide 3,4-diaminophenol (4.02 g, 91% yield) as a dark solid; MS (PB-PCI) C6H8N2O m/e calc 124.16; found 125 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:22]I.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:14]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:13][C:6]2[C:7](=[O:12])[N:8]([CH3:22])[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1CC=C(C)C)C(=O)NCCO2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CC=C(C)C)C(=O)N(C)CCO2
Temperature: 25 °C

Procedure:
601 mg of 8-methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[f][1,4]oxazepin-5-one was dissolved in 15 ml of N,N-dimethylformamide. Thereafter, 120 mg of sodium hydride was added to the reaction solution. Ten minutes later, 215 μl of methyl iodide was added to the reaction solution, and the obtained mixture was then stirred at room temperature. After completion of the reaction, a saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 513 mg of the subject compound.
Reaction SMILES: N1C=CC=N1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[CH3:16][C:14]1[S:13][C:11]2[N:12]=[CH:7][N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]=2[CH:15]=1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Agent: c1cn[nH]c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)ncnc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-pyrazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13](C=[CH:19][CH:20]=3)C(NC)=O)=[CH:10][C:5]2=[N:4][CH:3]=1.[N:21]1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:20]=[CH:19][N:21]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Product: Brc1cnc2cc(-c3ccncc3)ccn12

Procedure:
This compound is prepared analogously to 3-(3-Bromo-imidazo[1,2-a]pyridin-7-yl)-N-methyl-benzamide (Intermediate EA) by replacing (3-methylaminocarbonylphenyl)boronic acid (step EA2) with 4-pyridine boronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].OO.[OH:15]S(O)(=O)=O>[OH-].[Na+]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]([OH:15])=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Yield: 94 %

Procedure:
To 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 6.0 mmol) in 2.5M NaOH(aq) (10 mL) at 100° C. was added 35% H2O2 (12 mL) dropwise over 10 minutes and the mixture heated at reflux overnight. The solution was acidified with 10% H2SO4, extracted with EtOAc (2×100 mL), and the combined organic layers washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give 5-hydroxy-2-nitrobenzoic acid (1.03 g, 5.63 mmol, 94%). LC-MS (ESI) m/z 182 (M−H)+.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[Cl:24])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl[C:28]1[CH:33]=[N:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[Cl:24][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:2][C:28]3[CH:33]=[N:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:29]=3)=[CH:26][CH:25]=1)[O:16][CH2:15][CH2:14][CH:13]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Clc1cncc(-c2ccccc2)n1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(Cl)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cncc(-c5ccccc5)n4)cc3)c(Cl)cc21
Temperature: 60 °C
Yield: 92.2 %

Procedure:
Argon was bubbled through a tetrahydrofuran (665 μl) solution of ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.133 mmol; Example 45, step A) and 2-chloro-6-phenylpyrazine (25.4 mg, 0.133 mmol) at ambient temperature in a vial. Cesium carbonate (47.7 mg, 0.146 mmol), XPHOS ligand (12.7 mg, 0.0266 mmol), and tris(dibenzylideneacetone)dipalladium (0) (6.09 mg, 0.0066 mmol) were added. Argon was bubbled through the reaction for two minutes and the vial was capped. The reaction was heated to 60° C. (oil bath temperature) for 18 hours. The reaction was cooled to ambient temperature and applied to silica gel. Elution with a gradient of ethyl acetate/hexanes (20 to 85%) provided the title compound (65 mg, 92%) as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:15]([C:16]3[C:44]([F:45])=[CH:43][C:19]4[N:20](COCC[Si](C)(C)C)[C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5C(OC(C)(C)C)=O)=[N:22][C:18]=4[CH:17]=3)[CH2:14][CH2:13][C@@H:12]2[C:46]2[C:74]([F:75])=[CH:73][C:49]3[N:50](COCC[Si](C)(C)C)[C:51]([C@H:53]4[CH2:57][CH2:56][CH2:55][N:54]4C(OC(C)(C)C)=O)=[N:52][C:48]=3[CH:47]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@@H:15]([C:16]3[C:44]([F:45])=[CH:43][C:19]4[N:20]=[C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][NH:24]5)[NH:22][C:18]=4[CH:17]=3)[CH2:14][CH2:13][C@@H:12]2[C:46]2[C:74]([F:75])=[CH:73][C:49]3[N:50]=[C:51]([C@@H:53]4[CH2:57][CH2:56][CH2:55][NH:54]4)[NH:52][C:48]=3[CH:47]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc2cc([C@H]3CC[C@H](c4cc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c5cc4F)N3c3ccc(C(C)(C)C)cc3)c(F)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2[C@@H](c3cc4[nH]c([C@@H]5CCCN5)nc4cc3F)CC[C@@H]2c2cc3[nH]c([C@@H]4CCCN4)nc3cc2F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of di-tert-butyl (2S,2′R)-2,2′-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate (44 mg, 0.04 mmol) in dioxane (1 mL) was added 4 M HCl/dioxane (1 mL, 4.0 mmol) and the solution was stirred at 50° C. for 2 hours. The cooled solution was concentrated and placed under vacuum for 1 hour to provide the crude title compound that was used without purification.
Reaction SMILES: [OH-:1].[Na+].ClCl.C[C:6]([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:7]>O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:20][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=1[C:6]([OH:7])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To a solution of 7.3 moles (292 g.) of sodium hydroxide in 600 ml. of water is added ice to make the total volume of 1.75 liters. Chlorine gas is passed into the solution while maintaining the temperature below 10° C. until it is neutral to litmus, and 2.19 moles (87.6 g.) of sodium hydroxide dissolved in 200 ml. of water is added. The combined solution is warmed to 50° C., and 0.73 mole (230 g.) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is added slowly. The reaction mixture is stirred while heating until an exotherm begins about 75° C. and is thereafter maintained at about 80° C. by cooling. The mixture is stirred for about 16 hours at about 80° to 90° C. while monitoring the extent of the reaction by thin-layer chromatography. The excess hypochlorite is then destroyed by adding 75 g. of sodium bisulfite in 250 ml. of water, and the mixture is cooled to about 25° C. and carefully acidified with 10 percent hydrochloric acid. The light yellow solid product is collected by filtration, washed with water, and dried. A 94.5 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, m.p. 120° to 122° C., is obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1I
Product: O=C(Cl)c1ccccc1I

Procedure:
Ortho-iodobenzoic acid was reacted with excess thionyl chloride for 3 hours at reflux, and thionyl chloride was distilled off under reduced pressure to obtain ortho-iodobenzoic acid chloride. This was reacted with allyl alcohol in a dichloromethane solvent in the presence of a triethyl amine catalyst to obtain allyl ortho-iodobenzoate. The yield after purification by distillation or like process was repeated was 73%.