Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=2[CH3:35])=[O:28])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].Cl.[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46]>>[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH:46][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([N:7]([CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:34]([CH3:35])=[N:33][CH:32]=[N:31][C:30]=3[CH3:36])=[O:28])[CH2:19][CH2:18]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CN
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Yield: 40.9 %

Procedure:
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 129) (100 mg, 0.26 mmol) and glycine methyl ester hydrochloride (46 mg, 0.37 mmol) afforded COMPOUND 175 as a white solid (65 mg, 57%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.04-1.26 (m, 2H), 1.46-1.62 (m, 1H), 1.67-1.86 (m, 3H), 2.14-2.27 (m, 1H), 2.51 (s, 6H), 2.56-2.65 (m, 1H), 2.70-2.93 (m, 3H), 3.28-3.38 (m, 2H), 3.47-3.53 (m, 1H), 3.67-3.89 (m, 2H), 3.96-4.07 (m, 3H), 4.20, 4.21 (s, 2H), 6.43-6.59 (m, 3H), 7.42-7.58 (m, 4H), 7.64 (d, 3H, J=8.1 Hz), 8.49 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.50, 14.75, 21.97, 25.65, 28.42, 29.32, 30.43, 30.82, 36.04, 36.33, 39.99, 41.65, 43.55, 44.41, 48.02, 51.89, 52.40, 53.80, 55.71, 56.68, 60.17, 111.77, 112.07, 112.78, 118.78, 122.09, 128.89, 129.50, 129.65, 130.72, 130.84, 131.65, 140.87, 150.78, 157.58, 158.34, 163.12, 166.28, 166.90, 170.80, 181.11. ES-MS m/z 612 (M+H).
Reaction SMILES: [C:1]([N:5]([CH2:32][C:33]([O:35]CC)=[O:34])[C@H:6]([C:26]([O:28]C(=O)C)=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:5]([CH2:32][C:33]([OH:35])=[O:34])[C@H:6]([C:26]([OH:28])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN([C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)OC(C)=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N(CC(=O)O)[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
hydrolysing the ethyl ester and acetyl groups of t-butyl O-acetyl-N-carboethoxymethyl-thyroxine with sodium hydroxide in methanol and obtaining t-butyl N-carboxymethyl-thyroxine in the same process; and
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCI
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3 (Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>N1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)[CH:15]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.71 (dd, J=5.7, 4.1 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 8.15-8.12 (d, J=7.8 Hz, 1H) 8.44-8.42 (m, 1H), 8.50 (m, 1H), 8.60-8.56 (m, 1H), 8.93-8.91 (dd, J=1.7 Hz, 1H), 9.37-9.38 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)ccc2o1
Reaction time: 4 h

Procedure:
Ethyl 5-nitrobenzofuran-2-carboxylate (Aldrich, 8.0 g) was dissolved in a mixture of EtOH and THF, treated with 10% Pd/C (wet, Degussa type E101, Aldrich) and hydrogenated on a Parr apparatus at 35 psi for 4 h. The reaction mixture was filtered over Celite, washed with THF and EtOH and concentrated under vacuum to give crude solid product, 6.3 g which was used without purification. 1H NMR (CDCl3) 7.34-7.37 (m, 2H), 6.87 (d, 1H), 6.81 (dd, 1H), 4.41 (q, 2H, OCH2), 3.60 (broad s, 2H, NH2), 1.40 (t, 3H, OCH2CH3); m/z 206.39 [M+H]+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>CC#N>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (3.89 g, 54.8 mmol) is added to a mixture of 8.40 g (36.5 mmol) of 1-(2-bromoethyl)-4-nitrobenzene and 6.14 g (73.0 mmol) of NaHCO3 in 60 mL of CH3CN at 0° C. The mixture is stirred for 0.5 h at 0° C. and then at 25° C. overnight. The reaction is filtered, the insoluble material is washed with CH3CN and the filtrate and wash were combined. Darco is added, the solution is dried (MgSO4) and evaporated to a viscous red oil. Stirring this material with Et2O caused crystallization of the product. It is collected, washed with Et2O and dried in vacuo to give 7.60 g (95%) of a tan hygroscopic solid. 1H NMR (DMSO-d6) δ 8.22 (d, 2H, J=6.57 Hz), 7.62 (d, 2H, J=6.57 Hz), 3.47 (m, 2H), 3.25 (m, 2H), 3.10 (m, 4H), 1.94 (m, 4H); MS (ESI) m/z 221.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][C:8]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Temperature: 60 °C

Procedure:
33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of water and warmed to 60° C. 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxy-benzoic acid were introduced into the solution, and to this solution 29.55 g (0.14 mol) of 4-chloro-benzenesulfonyl chloride were added portionwise over 15 min . After cooling the mixture was filtered with suction, the residue was taken up in 1% sodium hydrogencarbonate solution, the solution filtered, and the product precipitated by addition of 1 N hydrochloric acid. 25.90 g (55%) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid of melting point (m.p.) 212-214° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:58][C:59]([F:63])([F:62])[CH2:60]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:60][C:59]([F:63])([F:62])[F:58])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol) and 1,1′-(azodicarbonyl)dipiperdine (123 mg, 0.49 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.122 mL, 0.49 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.177 mL, 2.32 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 8 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (41.8 mg, 0.085 mmol, 35%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:22])[N:7]([CH3:12])[C:6]=2[C:5]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Product: CCCN(CCC)c1ccc(Br)c2nc(Cl)n(C)c12
Yield: 99.1 %

Procedure:
A mixture of 4-bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (210 mg, 0.644 mmol) and phosphorus oxychloride (3.0, 32 mol) was refluxed for 18 h with stirring and concentrated to dryness under vacuum. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to afford 220 mg (99%) of the title compound. The residue was used for the next reaction without further purification.
Reaction SMILES: [BH4-].[Li+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13](OC)=[O:14])=[CH:9][CH:10]=2)[NH:5]1.O.Cl>O1CCCC1>[OH:14][CH2:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4](=[O:3])[NH:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2ccc(CO)cc2N1
Temperature: 50 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
Lithium borohydride (228 mg) was added to a suspension of methyl 2-oxoindolin-6-carboxylate (1.0 g) in tetrahydrofuran (10 ml) under ice-cooling and the mixture was stirred at 50° C. for 3 hours. Lithium borohydride (456 mg) was further added and the reaction mixture was stirred at 50° C. for 15 hours. Water was added to the reaction mixture under ice-cooling and the mixture was acidified with addition of conc. hydrochloric acid. It was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The resulted residue was triturated in methanol to give 6-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (172 mg) as a colorless powder. The mother liquid was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1 to ethyl acetate) to give the same (242 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH2:23])[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:14])=[O:13].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH:23][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:13])=[O:14]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Cl)C[C@@H]21
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N1C[C@H]2CC[C@H](Nc3ccc(C(F)(F)F)cn3)[C@H]2C1
Temperature: 86 °C

Procedure:
(3aR,4S,6aS)-2-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-amine (70 mg, 0.190 mmol) from Step B of Example 284, 2-bromo-5-(trifluoromethyl)pyridine (42.9 mg, 0.190 mmol), and triethylamine (0.079 mL, 0.569 mmol) were combined in ethanol (0.6 mL). The reaction was heated at 86° C. for 5 days and the solvent was evaporated in vacuo. The resultant material was purified using a 12 g silica gel cartridge with a gradient of 0-0.8% methanol (2 N ammonia)/dichloromethane over 20 minutes to give crude product. It was further purified by loading it onto 2×0.25 mm preparative thin-layer chromatography plate and eluted with 30% acetone/hexanes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50-8.52 (bs, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.03 (s, 1H), 7.96-7.98 (m, 1H), 7.75-7.78 (m, 1H), 7.54-7.59 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 4.30-4.42 (m, 1H), 3.89 (dd, J=10.2, 2.7 Hz, 1H), 3.57 (dd, J=10.2, 7.0 Hz, 1H), 3.43 (dd, J=9.9, 6.7 Hz, 1H), 3.39 (dd, J=10.0, 2.9 Hz, 1H), 2.68 (d, J=3.5 Hz, 2H), 2.13-2.20 (m, 1H), 1.90-1.97 (m, 1H), 1.59-1.66 (m, 1H), 1.40-1.48 (m, 1H); MS (ESI+) m/z 514 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:7]=[C:8]1\[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]\1=[O:18]>CO.C(Cl)(Cl)Cl.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1[nH]cnc1/C=C1\CCc2cccnc2C1=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1[nH]cnc1CC1CCc2cccnc2C1=O
Reaction time: 1 h
Yield: 5920.8 %

Procedure:
A mixture of (4) (1.39 g, 5.81 mmol) and Pd/BaSO4 (5 wt %, 0.47 g) in methanol and chloroform was hydrogenated at 50 psi for one hour. The reaction mixture was filtered through a bed of Celite, and washed with methanol. The solvents were removed under vacuum. The crude product was purified by chromatography on silica gel with 2 to 3% ammonia saturated methanol in dichloromethane to give 7-((5-Methyl-1H-imidazol-4-yl)methyl)-6,7-dihydroquinolin-8(5H)-one (5) as a yellow oil (0.830 g, 344 mmol, 59% yield).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]1[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[CH2:13][CH2:12]1>>[CH2:17]([O:16][N:15]1[CH:11]([N:1]2[CH2:9][CH2:8][N:7]([CH:11]3[N:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14](=[O:24])[CH2:13][CH2:12]3)[CH2:6][CH2:5][N:4]([CH:11]3[N:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14](=[O:24])[CH2:13][CH2:12]3)[CH2:3][CH2:2]2)[CH2:12][CH2:13][C:14]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(Br)N1OCc1ccccc1
Reactant: C1CNCCNCCN1
Product: O=C1CCC(N2CCN(C3CCC(=O)N3OCc3ccccc3)CCN(C3CCC(=O)N3OCc3ccccc3)CC2)N1OCc1ccccc1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 5-bromo-1-benzyloxy-2-pyrrolidone (1.2.6.11) and base.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]([CH2:29]Br)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:27]([CH2:29][N:14]2[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]([CH2:29][C:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:28])[C:10](=[O:21])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]2=[O:16])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(CBr)N1CCCC1
Product: CC(C)(C)OC(=O)NC1C(=O)N(CC(=O)N2CCCC2)c2ccccc2N(CC(=O)N2CCCC2)C1=O

Procedure:
Compound 14a is prepared in a manner similar to that used for preparation of Compound 14 h using previously prepared Compound 13 and pyrrolidinocarbonylmethyl bromide.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.Cl.[NH2:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])=[O:12])=[N:5][CH:4]=1)=[O:2]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: O=Cc1cnc(NCC(=O)O)s1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
Following the general procedure as described in Example 24, except using 2-(5-formylthiazol-2-ylamino)acetic acid, 1.00 HCl (582 mg, 2.62 mmol), (S)-tert-butyl 2-((S)-2-aminopropanamido)propanoate hydrochloride (661 mg, 2.62 mmol), 1-hydroxy-7-azabenzotriazole (175 mg, 1.29 mmol), CH2Cl2 (30 mL), EDC (588 mg, 3.07 mmol) and stirring at room temp for 18 h, 781.5 mg (78%) of the title compound is isolated by filtration as a light pink solid. LC/MS (Condition A): ret. T=2.64 min, (M+H)+ 385. 1H NMR (500 MHz, methanol-d4) δ ppm 9.66 (1 H, s), 7.97 (1 H, s), 4.37-4.53 (1 H, m), 4.21-4.32 (1 H, m), 4.16 (2 H, d, J=0.92 Hz), 1.47 (9 H, s), 1.38 (6 H, dd, J=15.72, 7.17 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1/[C:9](=[N:11]/[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH3:10].Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:17][C:14]([CH3:15])([S@:12]([NH:11][C@@:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:10])[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])[CH3:16]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Reactant: CCOC(=O)C(F)(F)Br
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-5-bromo-phenyl)-(E)-ethylidene]-amide and ethyl 2-bromo-2,2-difluoroacetate, the product (3R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluoro-5-bromo-phenyl)butanoate was obtained as an orange oil. MS (ISP): m/z=446.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.17 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:31]([CH2:39][CH3:40])[C:32]([O:34]C(C)(C)C)=[O:33]>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:31]([CH2:39][CH3:40])[C:32]([OH:34])=[O:33])=[CH:16][CH:17]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCc1cnc(N(CCc2ccc(OC(CC)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol and t-butyl 2-bromobutyrate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH2:12].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cn1c(CN)cc2ccccc21
Reactant: CCCC=O
Product: CCCCNCc1cc2ccccc2n1C
Yield: 10.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, (1-methyl-1H-indol-2-yl)methanamine (500 mg, 3.12 mmol) and butyraldehyde (310 μL, 3.43 mmol) were converted to the title compound (70 mg, 6%). 1H NMR (CDCl3) δ 7.62-7.54 (m, 1H), 7.36-7.27 (m, 1H), 7.27-7.16 (m, 1H), 7.17-7.03 (m, 1H), 6.50 (s, 1H), 4.05 (s, 2H), 3.77 (s, 3H), 2.82-2.70 (m, 2H), 1.60 (ddd, J=15.1, 7.5, 7.4 Hz, 2H), 1.45-1.16 (m, 2H), 0.96-0.87 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[C:4]([C:5](O)=[O:6])[CH:3]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[C:4]([C:5]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:6])[CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2nc(C(=O)O)cc(Cl)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N'-Carbonyldiimidazole (13.3 g) and 4-chloro-6-methoxyquinaldic acid (19.5 g) in dimethylformamide (100 ml) were stirred at room temperature for 2 hours. 5-Aminotetrazole was added and the mixture was stirred for 16 hours at room temperature. The solution was concentrated to 50 ml. and cooled. The solid was collected and dissolved in a warm mixture of dimethylformamide (50 ml) and dimethylaminoethanol (10 ml). The solid which crystallised was dissolved in water and the solution was acidified to pH 1 with dilute hydrochloric acid. The solid which separated was collected, washed with water and dried, m.p. 300° (d).