Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C@@H:10]([C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C@@H:11]([CH3:31])[C:12]([NH:14][C@@H:15]([CH2:24]C1C=CC=CC=1)[C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=[O:17])=[O:13].C(OC(N[C@H](C(N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(OC(C)(C)C)=O)=O)C(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.N[C@@H](C[C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[NH:92][CH:91]=1)C(N1CCCCO1)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:92]1[C:93]2[C:98](=[CH:97][CH:96]=[CH:95][CH:94]=2)[C:90]([CH2:24][C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([CH3:31])[C@@H:10]([O:9][CH3:8])[C@@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:17])=[CH:91]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1

Procedure:
The title compound was prepared in analogy to the synthesis of Intermediate 7 over two stages from Starting Compound 1 and (2S)-2-amino-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)propan-1-one trifluoroacetate (Intermediate 99).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH:16]=[CH2:17].Cl>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
H181 (200 mg, 1.33 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 213 mg, 5.33 mmol) and 3-bromoprop-1-ene (0.46 mL, 5.33 mmol). The reaction mixture was stirred for 5 h then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (160.5 mg, 63.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.1 & 2.4 Hz, 1H), 6.12-6.02 (m, 1H), 5.42 (dd, J=17.2 & 1.6 Hz, 1H), 5.29 (dd, J=17.2 & 1.6 Hz, 1H), 5.06 (s, 2H) and 4.57 (d, J=2.8 Hz, 2H) ppm; Mp: 79-81° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:10]2)[CH:5]=[N:4][C:3]=1[C:21]#[N:22].Cl.[CH3:24][C:25]1[CH:29]=[C:28]([NH2:30])[S:27][N:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:10]2)=[N:7][C:2]=1[NH:30][C:28]1[S:27][N:26]=[C:25]([CH3:24])[CH:29]=1)#[N:22]
Reactant: Cc1cc(N)sn1
Reactant: CN(C)C(=O)N1CCCC[C@@H](Nc2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(N[C@@H]3CCCCN(C(=O)N(C)C)C3)cnc2C#N)sn1
Temperature: 115 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
(R)-3-(6-Chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (509) (53 mg, 0.16 mmol) was combined with 3-methylisothiazol-5-amine hydrochloride (45 mg, 0.39 mmol), Pd(OAc)2 (14 mg, 0.062 mmol), BINAP (36 mg, 0.058 mmol), and Cs2CO3 (196 mg, 0.601 mmol). The solids were suspended in dioxane (10 mL degassed for 10 minutes with Nitrogen sparge) and the resulting suspension was stirred at 115° C. for 4 hours. The reaction mixture was cooled to RT, filtered, and purified by prep-TLC (EtOAc/DCM) to give (R)-3-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (510) (20 mg, 0.050 mmol, 31% yield).
Reaction SMILES: O.[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([N:14]3[CH:18]=[CH:17]N=C3)[NH:8][C:7]=2[CH:19]=1.[CH2:21](N)[CH2:22][CH2:23][CH2:24]CC>>[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:12])(=[O:13])[N:10]=[C:9]([NH:14][CH2:18][CH2:17][CH2:21][CH2:22][CH2:23][CH3:24])[NH:8][C:7]=2[CH:19]=1
Reactant: CCCCCCN
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2cc(Cl)c(Cl)cc21
Solvent: O
Product: CCCCCCNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
6,7-Dichloro-3-(imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate was treated with hexylamine according to the general procedure Method B to give the title compound; m.p. 282-286° C.; IR (KBr): 3332, 3173, 3074, 2956, 2930, 2854, 1637, 1580, 1562, 1464, 1241, 1168, 1143, 1132 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=O.S(Cl)(Cl)=O.[CH2:31](O)[CH3:32]>>[CH2:31]([O:25][C:23]([C:6]1[CH2:5][C:4]2[C:9](=[C:10]([F:19])[C:11]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=1)=[O:24])[CH3:32]
Reactant: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1=CN(CCF)c2c(cc(F)c(N3CCN(C)CC3)c2F)C1
Yield: 81 %

Procedure:
To a stirred suspension of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Fleroxacin; Belgian Patent No. 887,574) (35 g, 0.095 mol) in anhydrous ethanol (2.0 L) was added dropwise thionyl chloride (184 mL, 2.52 mol) over a 2-hour period. The solution was then heated at reflux and monitored by thin layer chromatography, until all starting material had been consumed (at this point a clear solution was obtained). The mixture was evaporated to dryness (36.3 g) and recrystallized from ethanol to give a white crystalline solid (30.4 g, 81% yield).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O)(O)(=O)=O.[NH2:16][OH:17].[OH-].[Na+]>O>[CH:1](=[N:16][OH:17])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=CC=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ON=CC=Cc1ccccc1
Temperature: 3 °C
Yield: 70 %

Procedure:
53.3 grams of cinnamaldehyde (0.40 mols) was added to a solution of 39.1 grams of hydroxylamine sulfate (0.48 mols) in 79.5 grams of water. The mixture was cooled in an icewater bath to 3° C. Then a solution of 17.7 grams of NaOH (0.44 mol) in 17.7 grams of water was added over a period of 25 minutes. The formed cinnamaldehyde oxime precipitated. The reaction mixture was warmed to roomtemperature and the crude product was filtered. After recrystallization from toluene pure cinnamaldehyde oxime was obtained as white crystals. Yield: 70%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[C:12]([CH3:21])[CH:11]=1.Cl.[CH3:24][C:25]([CH3:35])([CH3:34])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[CH3:24])[CH2:29][CH2:30]2)=[O:20])=[C:12]([CH3:21])[CH:11]=1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Oxalyl chloride (2.6 ml, 30 mmol) was added slowly to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (5.33 g, 24 mmol) in di-chloromethane (60 ml) and few drops of DMF at 0° C. The mixture was stirred for 2 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (30 ml) and added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (6.3 g, 26 mmol) in dichloromethane (45 ml) and DIEA (17 ml, 96 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (8.5 g, 96%).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>O1CCCC1>[S:1]1(=[O:2])(=[O:3])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:5][NH:4]1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)NCc2ccccc21
Temperature: 25 °C
Yield: 51.4 %

Procedure:
25.3 g (138 mM [sic]) of saccharin were added in portions over the course of 90 min to 7.1 g (187 mM [sic]) of lithium aluminum hydride in 400 ml of absolute tetrahydrofuran with vigorous stirring under nitrogen; during this, the temperature was maintained at room temperature by cooling in ice. After stirring overnight, the mixture was cooled in an ice bath and, while stirring vigorously, water was cautiously added dropwise, followed by 10% strength sulfuric acid. After the precipitated hydroxides had been filtered off with suction, washing with THF, the filtrate was concentrated, the residue was partitioned between methylene chloride and water and, after acidifying with 10% strength sulfuric acid, the organic phase was washed thoroughly with sodium carbonate solution. The organic phase was dried with sodium sulfate and filtered and then concentrated. 12.0 g (52%) of product of adequate purity were isolated.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH3:15]>C1COCC1>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:12])[CH2:13][CH2:14][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C

Procedure:
To a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde (4.64 g, 27.6 mmol) in THF (120 mL) at 0° C. was slowly added propylmagnesium bromide (2 M in THF, 28 mL). After the reaction was allowed to warm to room temperature over 1 h it was again cooled to 0° C. The reaction was quenched with 1 N HCl and partitioned between brine and MTBE. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the desired alcohol (1.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH-].[Na+]>[Zn].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2c[nH]c3ccccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2CNc3ccccc32)c1
Reaction time: 5 h
Yield: 48.6 %

Procedure:
Ten grams of the abovementioned 3-(3-methoxyphenyl)indole, 700 ml of 6N hydrochloric acid and 300 ml of ethanol were mixed and refluxed while 100 g zinc powder was added in small portions, and then the reflux was continued for 5 hours. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and extracted with chloroform. The resultant extract solution was concentrated to a residue which was then dissolved in diluted hydrochloric acid, and washed with ether. The aqueous layer was made alkaline with sodium hydroxide, extracted with chloroform, and dried and concentrated to obtain 4.9 g of 3-(3-methoxyphenyl)indoline.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[C:39]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[C:39]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=3[CH:33]=[CH:32][CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc2c1CCCC2
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 15.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.38 g, 2.09 mmol) in acetonitrile (4.4 mL) was treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol). After addition was complete, the mixture was stirred at 60° C. for 1.3 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.33 mL, 2.02 mmol) and acetonitrile (4.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (639 mg, 1.88 mmol) in acetonitrile (4.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded impure (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (102 mg, 15%) as an orange/red oil. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[O:21]=[C:20]1[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[NH:1]1
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)[nH]c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of ethyl N-(3-aminopyridin-2-yl)glycinate (18 g) in THF (200 mL) was added CDI (15 g) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residual crystals were washed with AcOEt to give the title compound (5.5 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[NH2:39][C:40]1[CH:44]=[CH:43][NH:42][N:41]=1>CN1CCCC1=O.[Cu]>[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([F:32])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]5[N:24]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:23]=[N:22][N:21]=5)[CH2:18][CH2:19]4)=[O:13])=[CH:9][NH:8][C:7]=23)[N:41]=1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: Nc1cc[nH]n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1ccn(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 160 °C
Yield: 15.9 %

Procedure:
A mixture of 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.2 mmol), potassium carbonate (26 mg, 0.2 mmol), copper (13 mg, 0.2 mmol) and 3-aminopyrazole (100 uL, 1 mmol) in N-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 5 h. Solvent was removed in vacuum and residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 1-(7-(3-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (15.9 mg) as a pale yellow solid; 1HNMR (500 MHz, DMSO) δ 8.34 (d, J=2.0 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.03 (s, 1H), 7.70-7.58 (m, 5H), 5.92 (d, J=2.5 Hz, 1H), 5.25 (m, 2H), 3.71 (m, 2H), 3.47 (m, 2H), 3.32 (m, 2H), 3.16 (m, 2H). LCMS: m/e 502 (M+H)+, ret time 1.26 min (method 3); and 1-(7-(5-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (8.8 mg) as a pale yellow solid; 1HNMR (500 MHz, CDCl3) δ 8.21 (m, 1H), 8.11 (bs, 1H), 7.60 (m, 6H), 6.94 (m, 2H), 5.52 (m, 1H), 3.71 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.16 (m, 2H); LCMS: m/e 502 (M+H)+, ret time 1.26 min (method 3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:3]=1.[C:20]([Si:24]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:25][CH:26]1[CH2:29][N:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:27]1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Si:24]([O:25][CH:26]1[CH2:29][N:28]([S:30]([NH:33][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[F:19])[N:3]=2)(=[O:32])=[O:31])[CH2:27]1)([C:20]([CH3:23])([CH3:21])[CH3:22])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)[Si](OC1CN(S(N)(=O)=O)C1)(c1ccccc1)c1ccccc1
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: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i) (0.16 g), 3-(tert-butyl-diphenyl-silanyloxy)-azetidine-1-sulfonamide (the product from step i) (0.17 g), tris(dibenzylideneacetone)dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (24 mg), cesium carbonate (0.16 g) and dioxane (8 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:9 to 2:8 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.12 g
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58].CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[O:58]=[CH:57][CH2:56][CH2:55][CH2:54][CH2:53][NH:52][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:21]
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: NCCCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A mixture of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (5 g, 13.5 mmol; prepared as described in Preparation 3), HATU (10.3 g, 27 mmol), 5-amino-1-pentanol (1.67 g, 16.2 mmol) and DIPEA (7.04 mL, 40.5 mmol) in 100 mL of DCM was stirred at room temperature for 1 hour. The reaction mixture was then washed with brine (100 mL), water (100 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in DCM (100 mL) and cooled down to −5° C. in an ice/brine bath. DIPEA (7.04 mL, 40.5 mmol) and DMSO (10 mL) were added to the solution, followed by sulfur trioxide pyridine complex (6.45 g, 40.5 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then washed with water (100 mL) and brine (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 4.88 g of the title intermediate (80% yield) as a semi-solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:6])=[O:5].NCC(CCCCCC(C)C)C(O)=O.C1(C(OC2C(C(C)(C)C)=CC(C)=CC=2C(C)(C)C)=O)CC1>>[NH2:1][CH2:2][CH:3]([CH2:7][C:8]1([CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:15][CH2:16]1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)CCCC(C)(C)CC(CN)C(=O)O
Agent: CC(C)CCCCCC(CN)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(OC(=O)C2CC2)c(C(C)(C)C)c1
Product: CC(C)CCCC1(CC(CN)C(=O)O)CC1

Procedure:
A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from 2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 228.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]>C(O)C.[Pd]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]
Reactant: C[C@H](Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 86.8 %

Procedure:
The compound (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (15.2 g, 45.9 mmol) was suspended in ethanol (150 mL), and palladium/carbon was added to perform the hydrogenation reaction. TLC test showed that the raw materials were completely reacted. The reaction liquid was filtered; the filtrate was concentrated under reduced pressure to remove ethanol to yield (S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (12 g, yield: 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([O:12][CH2:13][CH3:14])[N:3]=1.[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([O:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CO
Agent: [Na]
Product: CCOc1cc(C(Cl)(Cl)Cl)cc(OC)n1
Temperature: 62 °C
Reaction time: 8 h

Procedure:
To a solution of 54.99 grams (0.20 mole) of 2-chloro-6-ethoxy-4-(trichloromethyl)pyridine dissolved in 100 ml of methanol at 60° C. was rapidly added a solution of 6.90 grams (0.3 mole) of sodium metal dissolved in 150 ml of methanol. The mixture was heated to reflux for ~1 hour and then stirred at 62° C. overnight and thereafter refluxed for 8 hours followed by stirring at 62° C. overnight and then refluxed for 1 hour. A solution of 3.45 grams of sodium metal dissolved in 75 ml of methanol was added and the mixture brought back to reflux. The mixture was thereafter cooled and covered and allowed to sit ~64 hours (over a weekend). The methanol was removed by evaporation and the residue diluted with water and extracted with methylene chloride. The extract was washed with water, dried with sodium sulfate and the methylene chloride removed by evaporation. The desired 2-methoxy-6-ethoxy-4-(trichloromethyl)pyridine product was recovered by crystallization of the residue from methanol followed by recrystallization from ethanol. The product was recovered in a yield of 8.5 grams and melted at 36°-38° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and chlorine contents of 39.49, 3.54, 5.17 and 39.82 percent, respectively, as compared with the theoretical contents of 39.95, 3.72, 5.17 and 39.31 percent, respectively, as calculated for the above-named compound.