Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][C:27]1([CH3:36])[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][O:32][C:27]([CH3:26])([CH3:36])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: CC1(C)OCCN[C@@H]1C(=O)O
Product: COC(=O)C1=C(CN2CCOC(C)(C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 55 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (6.8 g, 15.3 mmol) was reacted with (S)-2,2-dimethylmorpholine-3-carboxylic acid (2.44 g, 15.3 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (4.4 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(P(=O)([O:7][CH2:8][CH3:9])OCC)#N.NC([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:24])[CH:22]=1)[C:17](O)=O)=O.FC(F)(F)C(O)=O.[NH2:39][C@@H:40]([CH2:54][C:55]1[CH:60]=[C:59](F)[CH:58]=[C:57](F)[CH:56]=1)[C@H:41]([OH:53])[CH2:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=1.C(N(CC)CC)C>ClCCl>[CH2:54]([C@H:40]([NH:39][C:8](=[O:7])[C:9]1[CH:17]=[C:16]([CH2:15][CH3:14])[CH:20]=[C:21]([C:23]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:24])[CH:22]=1)[C@H:41]([OH:53])[CH2:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[CH:46]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
Diethyl cyanophosphonate (0.132 mL, 0.870 mmol) is added to a mixture of 3-[(dipropylamino)carbonyl]-5-ethylbenzoic acid (IX, PREPARATION 21, 0.200 g, 0.720 mmol), (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII, EXAMPLE 175, 0.216 mg, 0.720 mmol), and triethylamine (0.121 mL, 0.870 mmol) in dichloromethane (3 mL). The mixture was stirred for 1 hour at 20-25 degrees C. Dichloromethane is then removed under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic phase is separated and is washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate is column chouromatographed (silica gel; methanol/dichloromethane, 5/95) to give the title compound, MS (ESI+) for C34H45N3O4 m/z (M+H)+=560.4; HOURMS (FAB) calculated for C34H45NO4+H=560.3488, found=560.3487.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3C(O)=N[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CI.C(=O)(O)[O-:27].[Na+].[CH3:31][N:32](C=O)[CH3:33]>>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[N:32]([CH3:33])[CH:31]=[CH:14][C:15](=[O:27])[CH:16]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C([O-])O
Reactant: Oc1ncccc1C1CCC2(CC1)OCCO2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Product: Cn1ccc(=O)cc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-2-ol (as prepared in example 10, Step B, 182 mg, 0.774 mmol) in dry DMF (5 mL) was added cesium carbonate (367 mg, 1.13 mmol) and methyl iodide (80 μL, 1.28 mmol). The reaction mixture was stirred at room temperature for 16 hours, poured onto saturated sodium bicarbonate solution and extracted with ethyl acetate. Purification by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) afforded 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-methyl-1H-pyridin-4-one as the more polar material along with the O-Methyl isomer as the less polar isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36](=O)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][N:25]([CH2:36][CH3:37])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: CC=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@@H]1F
Product: CCN1C[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-1-ethyl-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 322) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1)=[O:36]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccco2)C[C@@H]1C(=O)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Compound 2 (51 mg, 0.13 mmol) obtained in Example 2 was dissolved in dichloromethane (0.65 mL), and furan-2-carboxylic acid chloride (0.025 mL, 0.26 mmol) and pyridine (0.041 mL, 0.51 mmol) were added thereto, followed by stirring at 0° C. for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A residue obtained by concentrating the organic layer under reduced pressure was purified by preparative thin layer chromatography to obtain the title compound (65 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:14]=1[NH:15][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=1[OH:11]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc(Cl)cnc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)cnc1O
Yield: 42.9 %

Procedure:
Using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:34]4[CH:35]=[CH:36][N:31]=[N:32][CH:33]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1ccnnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with pyridazine-4-carboxylic acid to yield the title compound as light yellow solid. MS: 533.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:20][C:21]1[N:22]=[C:23]([Cl:39])[C:24]2[C:29](I)=[CH:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]=2[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:20][C:21]1[N:22]=[C:23]([Cl:39])[C:24]2[C:29]([C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[CH:10]=3)=[CH:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:25]=2[N:26]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Temperature: 85 °C
Yield: 58 %

Procedure:
2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1 equiv), 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), sodium carbonate (3 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.04 equiv) were combined in a 5:1 mixture of 1,4-dioxane and water (0.27 M). The mixture was heated to 85° C. for 1.5 h. The crude product was purified on silica gel (0-10% ethyl acetate in petroleum ether) to give an impure brown oil. The product was purified on silica gel (0-20% ethyl acetate in petroleum ether) to give the title compound (58% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.44 (m, 2H), 5.68 (s, 2H), 3.65 (m, 2H), 2.69 (s, 3H), 0.99 (m, 2H), 0.05 (s, 9H). MS (ESI) m/z 449.0 [M+1]+.
Reaction SMILES: CC(O)C.C([Cl:8])(=O)C.[NH2:9][C:10]1[C:15]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])[CH2:20][CH2:19]2)=[C:14]([Cl:36])[N:13]=[C:12]([CH3:37])[N:11]=1>C(OCC)C>[ClH:8].[ClH:36].[NH2:27][C@@H:25]([CH3:26])[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][C:15]2[C:10]([NH2:9])=[N:11][C:12]([CH3:37])=[N:13][C:14]=2[Cl:36])[CH2:19][CH2:20]1)=[O:35]
Reactant: CC(=O)Cl
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Product: Cl
Yield: 203.7 %

Procedure:
Heat IPA (154 mL) to 50° C. and add acetyl chloride (19.3 mL, 271 mmol) slowly due to an exothermic reaction. Stir the reaction at 50° C. for 10 min and then add tert-butyl N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (21.0 g, 45.3 mmol). Stir the reaction for 2 h monitoring via LCMS (low pH). Cool the reaction to RT and add diethyl ether (386 mL). Stir the slurry for 15 min. Filter the solids, washing with diethyl ether (2×50 mL) in a brisk manner as the material is hydroscopic. Filter the material and dry via filtration for 1 min, then in a vacuum drying oven at 50° C. overnight to give the title compound as a white powder (18.4 g). LC-ES/MS m/z (35Cl/37Cl) 326.1/328.2 (M+1). Counterion analysis by ion chromatography is consistent with the dihydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([CH2:22][CH2:23][CH3:24])=[C:15]([OH:25])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+].O>C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([CH2:22][CH2:23][CH3:24])=[C:15]([OH:25])[C:12]=3[C:13]=2[CH3:14])=[CH:26][CH:27]=1
Reactant: CCCc1cc(CCC)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCc1cc(CCC)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Temperature: 195 °C
Yield: 49.7 %

Procedure:
A mixture of 2 (p-methoxybenzoyl)-3 methyl-4-hydroxy-5,7-dipropylbenzofuran (0.30 gm; 0.80 mmoles), 99% hydrazine (0.2 mL), potassium hydroxide (0.40 gm; 7mmoles) in ethylene glycol (10 mL) was heated at 140° C. for a period of 2.5 hours and at 195° C. for one hour. The reaction mixture was cooled, poured into water, and extracted with ethylacetate. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 140 mg (50%) of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran, mp. 70°-72° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@H:4]([C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])[NH2:5].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[S:27][C:26]=2[CH:33]=1>>[ClH:21].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([C:30]([NH:5][C@@H:4]([C:6]([N:8]3[CH2:9][CH2:10][CH:11]([CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)[CH2:12][CH2:13]3)=[O:7])[CH2:3][S:2][CH3:1])=[O:31])[S:27][C:26]=2[CH:33]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CSC[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Product: CSC[C@@H](NC(=O)c1cc2ccc(Cl)cc2s1)C(=O)N1CCC(C2CCN(C)CC2)CC1
Product: Cl

Procedure:
Prepared from 1-(S-methyl-D-cysteinyl)-4-(1-methyl-piperidin-4-yl)piperidine and 6-chlorobenzo[b]thiophene-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. The HCl salt is prepared following General Salt Formation Method 1.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:17])[C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11](Cl)=[O:12])[CH:9]=1.[Cl-:19].[Al+3].[Cl-].[Cl-].O>C(=S)=S>[Cl:1][C:2]1([C:7]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([C:4]3([Cl:19])[CH2:5][CH:6]=[CH:2][S:3]3)=[O:12])[CH:9]=2)=[O:17])[CH2:6][CH:5]=[CH:4][S:3]1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: [Cl-]
Reactant: Clc1cccs1
Agent: [Al+3]
Solvent: S=C=S
Solvent: O
Product: O=C(c1cccc(C(=O)C2(Cl)CC=CS2)c1)C1(Cl)CC=CS1
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 2-chlorothiophene (0.128 mol) in 20 mL of carbon disulfide was added to a stirred suspension of isophthaloyl chloride (0.064 mol) and anhydrous aluminum chloride (0.1408 mol) in 100 mL of carbon disulfide. The reaction mixture was heated to reflux, stirred under nitrogen for 3 hours, and poured into 300 mL of water. The organic layer was separated immediately, then washed twice with 3.00 mL of 10% NaOH, twice with 300 mL of 5% HCl, and once with 500 mL of water. The product was recrystallized twice from ethyl acetate to form light yellow crystals in a 75% yield. Purity was determined by GC to be greater than 99.9%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC[CH2:52][C:53]([CH3:58])([CH3:57])[C:54]([O-:56])=[O:55].[C:59](=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:59][O:56][C:54](=[O:55])[C:53]([CH3:58])([CH3:57])[CH3:52])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OCOC(=O)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 7 ml acetone were added 40 mg chloromethylpivalate, 8 mg tetrabutylammonium iodide, 72 mg cesium carbonate and 61 μl triethylamine. The reaction mixture was refluxed for 4 h under argon. Additional 40 mg chloromethylpivalate, 8 mg tetrabutylammonium iodide, 72 mg cesium carbonate and 61 μl triethylamine were added and the suspension refluxed for another 7 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 75 mg MS (ES+): m/e=796.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 7) (18 g, 63.6 mmol) was dissolved in dry NMP (90 mL). 6-chloronicotinonitrile (13.21 g, 95 mmol) and DIPEA (22.20 ml, 127 mmol) were added, the mixture was stirred at 150° C. under a nitrogen atmosphere for 8 h, then allowed to stand overnight at room temperature. The solution was added to water (1 L) and the mixture extracted with EtOAc (2×400 mL). The organic layer was washed with water (2×500 mL), dried and evaporated in vacuo to give a brown foam. This brown foam was purified by silica gel column chromatography (750 g column, eluting with 0-100% EtOAc/cyclohexane). The appropriate fractions were combined and evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (18.7 g, 48.5 mmol, 76% yield) as a pale yellow solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[C:37]=1[S:44](Cl)(=[O:46])=[O:45]>CN(C)C=O>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:44]([C:37]1[C:38]([CH3:43])=[CH:39][C:40]([CH3:42])=[CH:41][C:36]=1[CH3:35])(=[O:46])=[O:45])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)s1
Reaction time: 5 h
Yield: 83.8 %

Procedure:
0.490 g (1.38 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonyl-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) were dissolved in 15 ml of anhydrous dimethylformamide. Under stirring, 0.47 ml of N,N-diisopropyl-N-ethylamine and 0.302 g of 2,4,6-trimethylphenylsulfonyl chloride were added. Stirring was continued for 5 hours until the reaction was complete (thin layer chromatography). The solvents were removed in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and with brine. After drying with anhydrous magnesium sulfate and filtration, the solvents were removed in vacuo to give 0.623 g of a yellow oil which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][C@H:14]([CH3:18])[NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH2:7][N:16]2[CH2:15][C@@H:14]([CH3:18])[NH:13][C@@H:12]([CH3:11])[CH2:17]2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cc(Br)ccc2O)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (1 g, 4.97 mmol) in DCM (50 mL) was added (2R,6S)-2,6-dimethylpiperazine (0.852 g, 7.46 mmol). The mixture was allowed to stir at RT for 40 min before sodium triacetoxyborohydride (1.582 g, 7.46 mmol) was added. The reaction was stirred at RT for 24 h. The mixture was diluted with DCM and washed with sat. NaHCO3 (aq), dried (MgSO4) and evaporated to give a white foam. This was purified by Biotage (eluent=2.5% 7M ammonia in methanol/DCM) to give the sub-title compound as a white solid. Yield: 1.32 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl>[CH2:45]([O:44][C:42](=[O:43])[O:20][CH2:19][N:11]1[C:12](=[O:18])[C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]([O:8][C:7]2[C:6]([Cl:21])=[CH:5][C:4]([N:22]3[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]3)=[CH:3][C:2]=2[Cl:1])=[N:10]1)[CH3:46]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), 4-N,N-dimethyaminopyridine (25.3 mg, 0.21 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol), in methylene chloride (3 mL) at 0° C. was treated with ethyl chloroformate (45 μL, 0.47 mmol). The reaction was stirred at allowed to gradually warm to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 1-10% methanol/methylene chloride) followed by reverse phase chromatography (Pursuit C-18 column, acetonitrile gradient with ammonium acetate) afforded carbonic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester ethyl ester (89.9 mg, 39%) as a white solid. ES+-HRMS m/e calcd for C21H18N6O7Cl2 (M+H+) 537.0687, found 537.0686.