Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84]/[C:85](/[CH:110]=[CH:111]/[C:112]1[C:113]([CH3:130])([CH3:129])[C:114]2[C:115]([N:128]=1)=[N+:116]([CH2:121][CH2:122][CH2:123][S:124]([O-:127])(=[O:126])=[O:125])[CH:117]=[C:118]([Cl:120])[CH:119]=2)=[CH:86]\[CH:87]=[C:88]1\[N:89]([CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[C:90]2[C:95]([C:96]\1([CH3:98])[CH3:97])=[CH:94][C:93]([S:99]([O-:102])(=[O:101])=[O:100])=[CH:92][CH:91]=2)([OH:82])=[O:81].[Na+].[Na+]>>[Cl:120][C:118]1[CH:119]=[C:114]2[C:113]([CH3:130])([CH3:129])[C:112](/[CH:111]=[CH:110]/[C:85](/[CH2:84][CH2:83][C:80]([O:82][N:70]3[C:74](=[O:75])[CH2:73][CH2:72][C:71]3=[O:76])=[O:81])=[CH:86]/[CH:87]=[C:88]3/[N:89]([CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:107])=[O:108])[C:90]4[C:95]([C:96]/3([CH3:97])[CH3:98])=[CH:94][C:93]([S:99]([O-:102])(=[O:100])=[O:101])=[CH:92][CH:91]=4)=[N:128][C:115]2=[N+:116]([CH2:121][CH2:122][CH2:123][S:124]([O-:127])(=[O:126])=[O:125])[CH:117]=1.[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)CCC(=O)O)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)CCC(=O)ON2C(=O)CCC2=O)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 36 is prepared analogously to compound 29 (Example 38), except that compound 19 is used as a starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:26])[C:17](Br)=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:27])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C-:28]#[N:29].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:26])[C:17]([C:28]#[N:29])=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:27])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(Br)cn3C2CC2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C#N)cn3C2CC2)CC1
Temperature: 202.5 °C
Yield: 94.3 %

Procedure:
A mixture of 4-(3-bromo-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-piperazine-1-carboxylic acid ethyl ester (11.0 g, 25.1 mmol), Cul (5.3 g, 27.6 mmol) and KCN (1.8 g, 27.6 mmol) in 110 mL of 1-methyl-2-pyrrolidinone (NMP) was heated at 200-205° C. for 16 hours. On cooling to room temperature, the reaction mixture was diluted with chloroform (250 ml) upon which a thick precipitate formed. The mixture was filtered over celite (2×) and the clear brown organic filtrate was washed with water/brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to a black oil. An off-white solid precipitated out by addition of hexane (150 ml) and ethyl acetate (300 ml). The solid was dissolved in chloroform, and activated charcoal and celite were added. The mixture was then filtered over celite. Evaporation of the solvent gave a white solid which was suspended in hot ethyl acetate and filtration afforded 9.1 g (94%) of 4-(3-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-piperazine-1-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>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]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Under nitrogen atmosphere, to a solution of 9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (0.10 g, 0.28 mmol) in tetrahydrofuran (0.84 mL) was added cyclopropyl magnesium bromide (1M solution in tetrahydrofuran, 0.84 mL, 0.84 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a pale yellow powder (82.4 mg, 0.21 mmol, 74%).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25](Cl)[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][O:30]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Reactant: ClCC1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC2CCN(CC3CCCO3)C2)c2ccc(I)cc2c1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in dimethyl formamide (3 mL) then tetrahydrofurfuryl chloride (1 mL) and potassium carbonate powder (400 mg, 22.2 mmol) were added. The reaction was stirred at 70° C. for 36 h. Water (15 mL) was added and the suspension was extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column using 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 181 mg (32% yield) of ethyl 6-iodo-4-oxo-1-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:14]=[CH:13][C:12](=O)[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23]1COCC1>C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]1[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:13]2[C@@H:14]1[CH2:23]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-3 (0.25 g, 0.76 mmol) in diethyl ether (3.8 mL) at 0° C. was added a solution of CH2N2 (7.6 mmol, made from treatment of 1-methyl-3-nitro-1-nitrosoguanidine with 40% KOH) in diethyl ether (5 mL) under nitrogen and the reaction mixture was stirred 2 h. The reaction was dried over magnesium sulfate and concentrated directly to yield an oil of >90% purity. The product was used without further purification. The oil was resuspended in THF (1.7 mL) at ambient temperature and to the mixture was added borane-tetrahydrofuran complex in THF (2.4 mL, 2.4 mmol, 1.0M solution). The reaction was stirred 15 h and quenched with methanol (2 mL). The combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by normal phase silica gel chromatography (0 to 65% EtOAc in hexanes) to afford the product (4-4) as an oil.
Reaction SMILES: C(=O)=O.[CH3:4][C:5]([CH3:7])=[CH2:6].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[O:10].C(=O)([O-])O.[Na+]>CC(C)=O>[OH:10][C@H:9]([CH2:6][C:5]([CH3:7])=[CH2:4])[C:8]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C[C@@H](O)C(=O)OC
Yield: 69.4 %

Procedure:
The above-obtained solution was cooled to -70° C. in a bath of dry ice and acetone, subsequently 0.56 g (10 mmoles) of 2-methyl-l-propene was bubbled into the cooled solution, and then 88 mg (1 mmole) of methyl glyoxylate was added to the solution. Then, the mixture was allowed to react at -30° C. for 15 hours. Subsequently, 10 ml of an aqueous sodium hydrogencarbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 0.10 g of methyl (R)-2-hydroxy-4-methyl-4-pentenoate. The yield was 72%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=O)[C:17]3[N:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:20][C:21]=3[N:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=P(Cl)(Cl)[Cl:32]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:18]1[C:17]2[C:21](=[N:22][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][C:16]=2[Cl:32])[N:20]=[CH:19]1)[CH3:28]
Reactant: CCOC(=O)Cn1cnc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cn1cnc2nc(N3CCNCC3)nc(Cl)c21
Temperature: 80 °C

Procedure:
A mixture of 0.6 g of 4-(7-ethoxycarbonylmethyl-6-oxo-6,7-dihydro-1H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 in 20 mL of POCl3 was heated to 80° C. for 4 h. The excess POCl3 was removed by concentration in vacuo. The residue was poured into ice water. The pH was adjusted by 5N NaOH. The solution was extracted with methylene chloride. The organic phase was concentrated in vacuo to afford 5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]([C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=CCCC(=O)Cl
Reactant: CCOC(=O)CCNCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)N(CCC(=O)OCC)CC(=O)OCC
Reaction time: 18 h

Procedure:
To the product of Step A, 1-a, (5.10 g, 25.1 mmol) in CH2Cl2 (50 mL) was added pent-4-enoyl chloride (2.83 mL, 25.1 mmol, 98% purity) and NEt3 (4.20 mL, 30.1 mmol) at 5° C. The reaction stirred about 18 hours and was then diluted with CH2Cl2, washed with aq Na2CO3 (2 M) and brine, dried (Na2SO4), filtered and concentrated to afford the product, 1-b.
Reaction SMILES: [S-2:1].[Li+].[Li+].F[C:5]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl.C(OCC)(=O)C>CS(C)=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:5]([SH:1])=[C:6]([C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1
Reactant: [S-2]
Reactant: O=C(c1ccccc1)c1cc(F)ccc1F
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1cc(F)ccc1S
Temperature: 120 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Lithium sulfide (3.5 g) (supplied from Aldrich) was added to a solution of 10.1 g of 2,5-difluorobenzophenone in 200 mL of DMSO, and stirred at 120° C. under a nitrogen atmosphere for 3 hours. Under ice cooling, 200 mL of 1 N hydrochloric acid was added to the reaction solution. Further 400 mL of ethyl acetate and 200 mL of water were added thereto, and the mixture was separated into two liquid phases. The organic layer was washed with 400 mL of water, and then washed with 200 mL of saturated brine. The organic layer was dried on sodium sulfate anhydrate and subsequently concentrated, to yield 10.54 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[C@@H:12]([C:13]([NH:15][C:16]2([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)=[O:14])[CH2:11][CH:10]2[CH:8]1[CH2:9]2.O[Li].O>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[C@@H:12]([C:13]([NH:15][C:16]2([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:18][CH2:17]2)=[O:14])[CH2:11][C@@H:10]2[C@H:8]1[CH2:9]2
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC4CC4N3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 89.4 %

Procedure:
The title compound (E29) (52 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-((3R)-2-(3-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (D146) (60 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C[Li].O>C(OCC)C>[C:11]1([S:8]([O:7][CH2:6][CH2:5][C:3]2[CH2:4][CH:2]=2)(=[O:10])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(OCCC1(Br)CC1(Br)Br)c1ccccc1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(OCCC1=CC1)c1ccccc1
Temperature: -78 °C
Yield: 70 %

Procedure:
A solution of 0.745 g (0.00150 mol) of 1,1,2-tribromo-2-(2-benzenesulfonyloxyethyl)-cyclopropane in 4 ml of diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling to −78° C. in a dry ice/acetone bath, 23.45 ml (0.00450 mol) of 1.4 M methyl lithium in diethyl ether was added slowly via syringe. After 15 minutes warmed to 0° C. in an ice water bath then returned to −78° C. for about 30 minutes before 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield >0.155 g of 70% pure 2-(2-benzenesulfonyloxyethyl)-cyclopropene contaminated with 30% 1-(2-hydroxethyl)cyclopropene as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:6]([O:5][C:1]([NH:2][N:3]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl carbazate (10.0 g, 75.64 mmol) in 99% ethanol (100 ml) was added benzaldehyde (7.64 ml, 75.64 mmol) and the mixture was stirred for 60 min. The mixture was cooled to 0° C., filtered and the precipitate was washed with cold ethanol and dried to give 13.47 g (81%) of N'-benzylidenehydrazinecarboxylic acid tert-butylester as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]1SCCCS1.[CH:17]1([CH:23]=[CH:24][C:25](OCC)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>[Ni]>[CH:17]1([CH:23]2[CH2:11][C:4]3[C:5](=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=3[O:2][CH3:1])[C:25](=[O:26])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(C2SCCCS2)c1OC
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2=O

Procedure:
2 (2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, Method B, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, were condensed as described in Step 2 of Example 1, Method B. The adduct was treated with Raney nickel and sodium hydroxide to give the corresponding acid. The acid was cyclized with polyphosphoric acid as described in Step 6 of Example 1, Method A, to give 3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydro naphthalenone. This ketone was treated with trimethylsilylcyanide in the presence of aluminum chloride and reduced with lithium aluminum hydride as described in Step 1 of Example 2 to give 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydro-naphthalene. The hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of Example 2 to give 1-aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-dimethoxy-naphthalene hydrochloride, m.p. 178°-179° C., 1H NMR (d6DMSO) delta 1.0-1.4 (m, 7H), 1.5-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 (s, 3H), 3.81 (s, 3H), 5.8 (d, 1H), 6.6 (m, 2H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH2:18][CH3:19])[CH3:17])[C:14]=2[CH:15]=1.NCC1[C:27](=[O:36])NC(C)=CC=1CCC.[OH-].[Na+]>CN(C=O)C.O>[Br:6][C:7]1[CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]2[C:11]([CH:27]=[O:36])=[CH:12][N:13]([CH:16]([CH2:18][CH3:19])[CH3:17])[C:14]=2[CH:15]=1
Reactant: CCC(C)n1ccc2c(C(=O)OC)cc(Br)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)n1cc(C=O)c2c(C(=O)OC)cc(Br)cc21
Reaction time: 0.5 h

Procedure:
POCl3 (8.3 g, 54.3 mmol) was added at 0° C. to anhydrous DMF (230 mL) in a round bottom flask and stirred for 30 min. Then a solution of methyl 6-bromo-1-sec-butyl-1H-indole-4-carboxylate, 5 (14 g, 45.3 mmol) in DMF (60 mL) was added to the reaction mixture at 0° C. and stirred at room temperature for 2.5 h. The reaction mixture was diluted with cold water, adjusted pH˜8 using with 2N NaOH solution and extracted with ethyl acetate (4×200 mL). The combined organic layer was washed with cold water (2×100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-1-sec-butyl-3-formyl-1H-indole-4-carboxylate, 6 (15.2 g, 99%) as pale yellow solid. This was used as such in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ (0.831-0.859 (m, 3H), 1.515-1.574 (d, J=6.8 Hz, 3H), 1.729-1.972 (m, 2H) 3.997 (s, 3H), 4.394-4.445 (m, 1H), 7.756 (d, J=1.2 Hz, 1H), 7.958 (d, J=2 Hz, 1H), 8.079 (s, 1H), 10.452 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:43]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=5[O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:42][CH:40]([F:41])[CH2:39][O:38][C:29]1[CH:30]=[C:31]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:43]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c(OCC(F)F)c1

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.285 g, 0.465 mmol) and trifluoroacetic acid (2 mL) in a manner analogous to Example 312 to give product (0.203 g, 85%). MP=128-131° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.82 (d, 1H), 7.95 (d, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.40 (d, 1H), 7.32 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.22 (br m, 1H), 4.53 (m, 2H), 2.84 (br m, 8H), 2.67 (br m 1H), 2.50 (s, 3H). MS=514 (MH)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[N:16][C:5]=2[N:4]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:3]1=[O:27].C(N(CC)CC)C.ON1C2=NC=CC=C2N=N1.[C:45]([O:49][C:50]([NH:52][C@@H:53]([CH3:57])[C:54](O)=[O:55])=[O:51])([CH3:48])([CH3:47])[CH3:46].Cl.CN(C)CCCN=C=NCC>ClCCl>[Si:20]([O:19][CH2:18][CH2:17][N:4]1[C:5]2[N:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]([NH:1][C:54](=[O:55])[C@@H:53]([NH:52][C:50](=[O:51])[O:49][C:45]([CH3:47])([CH3:46])[CH3:48])[CH3:57])[C:3]1=[O:27])([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2ncccc2-c2ccccc21
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Cool a mixture of 7-amino-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (36.3 g, 89.9 mmol), dichloromethane (360 mL), triethylamine (16.3 mL, 116.9 mmol), 3-hydroxytriazolo[4,5-b]pyridine (15.9 g, 116.9 mmol), and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (22.5 g, 116.9 mmol) to 0° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.4 g, 116.9 mmol) and after 5 minutes allow to warm to ambient temperature overnight. Wash with water (500 mL×2), saturated aqueous sodium bicarbonate solution (2×300 mL), brine (300 mL), and then dry over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with isopropyl alcohol:hexane (5:95 to 10:90) to give the title compound as a white foam (43.14 g, 77.77 mmol, 86.50%). MS (m/z): 555 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(O)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(O)c4)c(C(=O)O)s3)c2cc1OC
Yield: 6 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-hydroxyphenylboronic acid (20.7 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-hydroxy-phenyl)-thiazole-5-carboxylic acid (2.4 mg, 6%) as a white solid. MS m/z 398 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S-:12][C:13]#[N:14].[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>O>[S:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:13]#[N:14]
Reactant: N#C[S-]
Reactant: CCCCCCCCCCBr
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCSC#N
Reaction time: 2 h

Procedure:
A mixture of 100 grams (0.45 mole) of 1-bromodecane, 160 grams (1.98 moles)of sodium thiocyanate, 50 ml water and 10 grams of tricaprylylmethylammonium chloride was heated to 88°-105° C with stirring over a period of 2 hours. Examination of the reaction mixture by gas liquid partition chromatography showed that 100% conversionof the 1-bromodecane had occurred to give 1-thiocyanodecane.