Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Product: Cc1nc2c(N)nc3c(c2n1CCCCNC(=O)N1CCOCC1)CCCC3
Yield: 79.7 %

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (100 g, 3.7 mmol) was reacted with 4-morpholinecarbonyl chloride (0.43 mL, 3.7 mmol) to provide 1.14 g of N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide as an off white solid, m.p. 133.6-134.6° C. Analysis: Calculated for C20H30N6O2. 1.1H2O: %C, 59.12; %H, 7.99; %N, 20.68; Found: %C, 58.77; %H, 7.53; %N, 20.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: CC(C)N
Product: CC(C)NC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 23.9 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid and isopropylamine as the raw materials, the same operation as the example 212(2) gave the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:81]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
12.8 mg (13.9 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 10.9 mg (41.8 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 10.8 mg (59% of theory) of the title compound were obtained as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([O:23]C)=[O:22])[C:16]([C:17]([O:19]C)=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]2=[CH:13][CH:14]=[C:15]([C:21]([OH:23])=[O:22])[C:16]([C:17]([OH:19])=[O:18])=[C:11]2[N:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
A mixture of dimethyl 1-benzyl-2-methyl-4,5-benzimidazoledicarboxylate (5.50 g, 16.2 mmol), methanol, 10N sodium hydroxide (13 mL, 130 mmol) and Water is stirred for 4 hours at 70° C., cooled, acidified to pH 4 with hydrochloric acid and filtered to afford the title product as an off-white solid (4.94 g, 98.4%), mp 224°-226° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
A stirred solution of N,N-dimethylformamide (1.68 ml) was added dropwise slowly with phosphorus oxychloride (0.9 ml, 9.65 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.29 g, 8.77 mmol) in 10.5 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (5 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (989 mg, 3 steps 31.7%) as a red oil which was used as such.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:13][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(OC)ccc1CBr
Temperature: 77 °C
Yield: 99.8 %

Procedure:
Step 1 A suspension of methyl 5-methoxy-2-methylbenzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.037 g, 5.83 mmol) and benzoyl peroxide (81 mg, 0.333 mmol) in tetrachloromethane (10 mL) was heated at 77° C. for 3 h. The mixture was diluted with DCM, washed with NaHCO3 (aq), dried and concentrated to provide crude methyl 2-(bromomethyl)-5-methoxybenzoate as a light yellow solid (1.435 g), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.48 (1 H, d, J=2.64 Hz), 7.37 (1 H, d, J=8.36 Hz), 7.02 (1 H, dd, J=8.58, 2.86 Hz), 4.93 (2 H, s), 3.95 (3 H, s), 3.85 (3 H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>S1(CCCC1)(=O)=O.O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
2,4-Dihydroxybenzoic acid (48.0 g), anhydrous potassium carbonate (21.5 g), benzyl chloride (39.4 g) and dry sulpholane (400 ml) were heated together, with stirring, at 100° C. for 20 hours. The mixture was then poured into water (2 liters), the resulting oil was separated and the aqueous layer extracted with diethyl ether (300 ml). The ether extract was evaporated and its residue was combined with the said oil layer and washed with water (500 ml) to remove sulpholane, and then was washed with brine, the aqueous washings were extracted with diethyl ether (400 ml), and the combined oil and ether extract were dried and evaporated to give crude benzyl 2,4-dihydroxybenzoate (64 g), m.p. 83°-88° C. This ester (20 g) was treated with anhydrous potassium carbonate (17.0 g) and benzyl chloride (22.8 g) in dry sulpholane (300 ml) and the mixture was stirred and heated at 140° C. for 3 hours. It was allowed to cool and was then poured into water (1500 ml) and the mixture was neutralised to pH 7 by treatment with hydrochloric acid. The precipitated crude benzyl 2,4-dibenzyloxybenzoate was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 400 ml) and ethanol (50 ml) for 10 hours. The solution was allowed to cool, and was then diluted with a large volume of water and acidified to pH 1 by treatment with hydrochloric acid (2N) to give a white solid which was filtered off and recrystallized from ethanol to give 2,4-dibenzyloxybenzoic acid (16.8 g), m.p. 126°-128° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]1[C@H:23]([C:24]([O:26]CC)=[O:25])[CH2:22][C:17]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]2([S:18][CH2:19][CH2:20][S:21]2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CN1C(=O)CNC(=O)OCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2)OCc1ccccc1

Procedure:
Hydrolyze 1.43 g of 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro [4.4]nonane-8(S) -carboxylic acid, ethyl ester (prepared as described in paragraph B next above) with sodium hydroxide as described in Example 23 to obtain 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, a colorless oil, [α]D26 -7.9°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:19]1([NH:18][C:15]([CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid (EXAMPLE 40, 30 mg, 0.12 mmol) in DMF (2 mL) was added aniline (12 μL, 0.13 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (41 μL, 0.24 mmol). After 5 min, EDCI (29 mg, 0.15 mmol) was added, and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. m/z (ES+)=329 [M+H]+; RT=3.17 min.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzamide (0.50 g) in ethanol (10 mL) was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-(2-hydroxybenzyl)benzamide (0.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)=[N:10]1.Cl.[NH:34]1[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CN3CCOC(C(=O)O)C3)N2)n1
Yield: 20.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.13 g, 20%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.CN(C)C=O.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Temperature: 55 °C

Procedure:
2,4-Dichloro-5,6-dimethyl-3-nitropyridine (1.00 g), anhydrous N,N-dimethylformamide (5 ml), triethylamine (0.63 ml), and 2-phenoxyethylamine (0.59 ml) were combined and the resulting mixture was heated to 55° C. for 24 hours. Thin layer chromatography (TLC) monitoring of the reaction indicated that it was complete. The solvent was removed under reduced pressure and the remaining oil was dissolved in dichloromethane (DCM) and washed once with water. Following 2 additional extractions with DCM, the organic layers were combined, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The product was passed through a column using 20/80 ethyl acetate/hexane as the eluant. NMR analysis of the resulting yellow solid indicated sufficient purity for use in the next step.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:36][C:33]1[CH:32]=[N:31][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:25][CH2:26]2)=[N:35][CH:34]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ncc(F)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(OCC3CCN(c4ncc(F)cn4)CC3)cn2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 0.15 g, 0.60 mmol), [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methyl methanesulfonate (0.234 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at 100° C. in a preheated oil bath for 2.5 h. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a light brown solid. The crude product was purified by chromatography on a silica gel column eluted with 1:30 acetone/CH2Cl2 then 1:20 acetone/CH2Cl2 to give 0.132 g (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.30 (s, 1H), 8.18 (s, 2H), 8.11 (d, 2H, J=8.0 Hz), 8.02 (d, 2H, J=8.1 Hz), 4.80-4.65 (m, 2H), 4.25 (d, 2H, J=6.6 Hz), 3.07 (s, 3H), 3.00-2.85 (m, 2H), 2.10-2.05 (m, 1H), 2.00-1.85 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([NH:33][CH3:34])=[O:32])[CH:25]=3)=[CH:11]2)=[N:6]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([NH:33][CH3:34])=[O:32])[CH:25]=3)=[CH:11]2)=[N:6]1
Reactant: CNC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2ccc3nn(CCOC)cc3c2)ccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)Nc1cc(CNc2ccccc2C(=O)Nc2ccc3nn(CCO)cc3c2)ccn1
Yield: 53.4 %

Procedure:
50 mg (0.11 mmol) of N-[2-(2-methoxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide is introduced into 5 ml of methylene chloride and mixed drop by drop with 0.56 ml of boron tribromide (1 mol in methylene chloride) under argon and in a moisture-free environment at −78° C. It is stirred for 15 more minutes, the cold bath is removed, and then it is stirred for another 2 hours. Then, it is mixed with water, the methylene chloride is drawn off, it is made alkaline with sodium bicarbonate solution, and it is extracted twice with 15 ml of ethyl acetate each. The collected organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with a gradient of methylene chloride:ethanol=100:0 to 90:10 as an eluant, and 27 mg of N-[2-(2-hydroxy-ethyl)-2H-indazol-5-yl]-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide is obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>C(#N)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
Benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1″ (2.000 g; 6.579 mmol) is dissolved in acetonitril (10.000 ml). N-Methylpiperazine (1.460 ml; 13.158 mmol) is then added. The reaction mixture is stirred for 40 min at 160° C. in a Biotage XP Sixty microwave. The reaction mixture is poured into water and extracted with 3×50 ml DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[N:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][N:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 20 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g). In a manner similar to the method described in Examples 1e, rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2-methyl-1-propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]#[N:12])[CH:5]=1.[Li+].[OH-].CO>O1CCCC1>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([I:10])[CH:7]=1)[C:3]([OH:13])=[O:2])#[N:12]
Reactant: COC(=O)c1cc(I)cc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(I)cc(C(=O)O)c1
Yield: 94 %

Procedure:
A solution of methyl-3-cyano-5-iodobenzoate (640 mg, 2.3 mmol) in tetrahydrofuran (8 mL) was treated with 0.5M LiOH (5.5 mL, 2.75 mmol) and methanol. The reaction mixture was heated at reflux for 1 hour. The solvent was concentrated in vacuo and the mixture treated with 1N HCl. The resulting white precipitate was filtered and the filtrate was extracted with dichloromethane. The residue and the extracted filtrate were combined and concentrated in vacuo to afford 590 mg (94%) of 3-cyano-5-iodobenzoic acid, as a white solid.