Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCCCCCCc1ccccc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.49 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 25 ml of acetonitrile is mixed with 176 mg (0.73 mmol) of (6-bromohexyl)benzene and 101 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 364 mg (0.48 mmol, 98% of theory, purity 76%) of a yellowish oil are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][OH:27])[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][O:27][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(CO)C[C@@H]12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (290 mg, 0.72 mmol) and Et3N (144 μL, 1.04 mmol) in CH2Cl2 (6.5 mL) at 0° C. under nitrogen atmosphere was added methanesulfonyl chloride (81 μL, 1.04 mmol) and the mixture was stirred at RT for 1 h. Et3N (48 μL, 0.35 mmol) and methanesulfonyl chloride (27 μL, 0.35 mmol) were again added and the mixture was further stirred for 0.5 h to complete the reaction. A saturated aqueous solution of NaHCO3 was added, the layers were separated and the aqueous layer extracted with CH2Cl2 (×2), dried (Na2SO4), filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, Rf (EtOAc)=0.65; MS (UPLC/MS): 477.3/479.3 [M+H]+, 521.3/523.3 [M+HCOO]—
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11][C:10]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[OH-].[Na+]>O.C(O)(C)C>[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:19])(=[O:20])[N:11]([CH3:5])[C:10]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,425 ml (15 mol) of dimethyl sulfate are added at between 10° and 15° C. to a solution of 2,833 g (10 mol) of isopropyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 440 g (11 mol) of sodium hydroxide in 4 l of water and 11.3 l of isopropanol. The mixture is maintained with stirring for 4 hours at room temperature, diluted with 28 l of water and cooled to 0°-5° C. The precipitate obtained is centrifuged, washed with cold water and dried, 2.675 g (90%) of a white or slightly pink solid, m.p. 102°-3° C. (104°-5° C. from methanol), being obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[OH:14].C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>CN(C=O)C>[CH2:7]([N:5]1[CH2:4][C@@H:3]2[C@@H:2]([NH:1][C:20](=[O:21])[O:14]2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@H]1CN(Cc2ccccc2)C[C@H]1O
Solvent: CN(C)C=O
Product: O=C1N[C@H]2CN(Cc3ccccc3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
(3R,4S)-4-Amino-1-benzylpyrrolidin-3-ol (6 g, 31.4 mmol) in DMF (100 mL) was treated with CDI (5 g, 31.4 mmol) and the reaction mixture was stirred at r.t. for 18 h. The reaction was concentrated in vacuo and azeotroped with heptane. The residual oil was chromatographed on silica with a mixture of dichloromethane and methanol (gradient elution 0-10% methanol), yielding a colourless oil (6 g) which crystallized on standing. δH (DMSO-d6) 7.58 (1H, s), 7.29 (5H, m), 4.96 (1H, dd, J 7.9, 4.5 Hz), 4.16 (1H, dd, J 7.7, 4.9 Hz), 3.59 (2H, m), 3.00 (1H, d, J 11.1 Hz), 2.76 (1H, m), 2.19 (1H, dd, J 11.3, 4.5 Hz), 2.08 (1H, dd, J 10.2, 4.9 Hz).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](N)=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH2:28]([O:27][C:25]([C:9]1[N:8]=[C:7]2[N:6]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5](=[O:23])[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]2=[CH:11][CH:10]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(N)ccc21
Solvent: c1ccncc1
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(C(=O)OCC)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 1 g. of amino product produced in Example 35 in 20 ml. of dry pyridine. Cool in an ice-bath and stir while slowly adding 300 mg. of ethyl chloroformate. Allow the reaction mixture to stand at room temperature overnight. Pour the reaction mixture into ice-water and collect the crude product by filration. Crystallize the crude product from dimethyl formamide-ether.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C[N:35](C=O)C>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:35]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in DMF (5 mL) under Ar. K2CO3 (0.425 g, 3.080 mmol, 4 eq) was added followed by the addition of (1S,4S)-(+)-1-Aza-5-oxabicycle[2,2,1]-heptane hydrochloride (0.314 g, 2.320 mmol, 3 eq). The reaction mixture was stirred at 80° C. for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.150 g (50%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 391 (M+1); Anal. Calcd for C24H26N2O3.1HCl.0.90H2O: C, 65.05; H, 6.55; N, 6.32; Found: C, 65.05; H, 6.60; N, 6.13.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][C:28]#[CH:29].C(O)(=O)C(O)=O.CC(C)=O>CC#N>[CH2:29]([N:4]1[CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:1][CH2:2][CH2:3]1)[CH2:28][C:27]#[CH:26]
Reactant: C#CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 67.5 °C
Reaction time: 15 h

Procedure:
Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[N:23]([CH3:32])[C:22]1=[O:33].C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@H:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[N:23]([CH3:32])[C:22]2=[O:33])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CCc2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1

Procedure:
100 mg of 19 (0.39 mmol), 88.42 mg of 8a (0.39 mmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2.0 ml of THF are successively introduced into a Wheaton tube, with agitation and under an argon atmosphere. The agitation is maintained at AT for 24 h. The reaction medium is directly evaporated to dryness. The crude is chromatographed on a silica cartridge (12 g, eluent EtOAc), and 60 mg of expected product Ex6 (white solid) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O.CCOC(C)=O>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:23](=[O:26])(=[O:25])[N:24]=1
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in DMA (15.0 mL) was added sulfamoyl chloride (2.68 g, 23.21 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 2 hrs and the solution was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%). The intermediate was dissolved in EtOH (25.0 mL) and aq.NaOH (2.0N, 5.0 mL) was added at room temperature. The reaction mixture was then refluxed overnight then cooled to 0° C. and neutralized carefully with 1 N HCl. The precipitate was collected by filtration and was recrystallized with 20% water/EtOH to provide the title compound as a white solid (730 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6, room temperature) δ0.86 (t, J=7.6 Hz, 3H), 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J=13.6 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, isomer), 4.50 (t, J=10 Hz, 1H), 5.16 (t, J=4.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.68 (s, isomer), 7.77 (s, 1H), 8.23 (s, 1H), 8.36 (s, isomer), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ0.88 (t, J=7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 (m, 7H), 1.77 (d, J=11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J=10 Hz, 1H), 5.00-5.03 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.81 (s, 2H), 10.64 (s, 1H). MS 381 (MH+).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][C:15]=2[F:24])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: CNC(=O)c1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and 4-amino-3-fluoro-N-methylbenzamide [Anker et al, Helv. Chim. Acta., 67(3), 706-716 (1984)] were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (100% EtOAc as eluant), 3,4-difluoro-2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-benzoic acid was isolated as a pale, yellow-orange solid; m.p. (EtOAc/MeOH) 242-244° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (v br s, 1 H), 9.28 (br s, 1 H), 8.36 (br d, J=4.5 Hz, 1 H), 7.88-7.80 (m, 1 H) 7.69 (dd, J=12.5, 1.7 Hz, 1 H), 7.60 (dd, J=8.5, 1.5 Hz, 1 H), 7.19 (dd, J=16.7, 9.3 Hz, 1 H), 7.01 (ddd, J=8.6, 8.6, 5.8 Hz, 1 H), 2.77 (d, J=4.4 Hz, 3 H). Anal. calcd. for C15H11F3N2O3: C, 55.6; H, 3.4; N, 8.6. Await Found.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8](=[N:11][NH2:12])[NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cccc(C#N)n1
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(N)=NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
11.97 g (101.4 mmol) 6-methylpyridine-2-carbonitrile are dissolved in 25 mL ethanol. After addition of 36.3 mL (304.05 mmol) hydrazine hydrate (w=30%) the reaction mixture is stirred for 24 hours at room temperature. The precipitated product (K1=1.45 g) has been filtered off and the filtrate is evaporated to ⅓ of its volume. After dilution with water the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine and dried (Na2SO4). The solvent has been removed yielding a K2 (11.11 g) of the desired product. The overall yield is 78.9%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:18][O:19][CH2:20]Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:10][CH2:18][O:19][CH3:20])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1c(Br)cccc1C=O
Reaction time: 0.75 h

Procedure:
To 3-bromo-2-hydroxybenzaldehyde (1.33 g, 6.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.81 g, 8 mmol) then chloromethyl methyl ether (0.56 g, 7 mmol). The mixture was stirred for 45 minutes and partitioned between CH2Cl2 and saturated NaHCO3(aq). The crude material was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to afford the titled compound.
Reaction SMILES: S(C)C.[CH2:4]([Mg]Br)[CH3:5].[B-](F)(F)(F)[O+](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]=[CH:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]([CH2:4][CH3:5])[CH2:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CC(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC[Mg]Br
Agent: C[O+](C)[B-](F)(F)F
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
CuBr2.SMe2 (19.13 g, 93.1 mmol) was placed into a flame-dried flask along with THF (250 ml). The mixture was cooled to −78° C. and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93,1 mmol) and the mixture stirred for 5 minutes. Ethyl 1-(4-chlorophenylsulfonyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (103; 8.0 g, 23.3 mmol) was added via syringe pump over a 2 hour period while maintaining −78° C. bath temperature. The reaction was stirred for 4 hours and quenched with a 1:1 solution of 2% NH4Cl/NH4OH. An equal amount of EtOAc and water was added and the mixture was filtered to remove solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na2SO4 and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using EtOAc/hexanes gradients to yield 5.84 g (67%) of a mixture of cis/trans (4:96) isomers.
Reaction SMILES: O[C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:28]([C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: N#Cc1cccc2c1CCC[C@@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (3.00 g, 17.32 mmol) in toluene (16 mL) under N2, was cooled to 0° C. DPPA (9.53 g, 34.64 mmol) was added, followed by dropwise addition of DBU (3.16 mL, 20.78 mmol) over 20 min. The mixture was stirred at 0° C. for 4 h then slowly warmed to room temperature over 2 h and then concentrated. The resulting crude mixture was diluted with EA and washed with NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, and chromatographed (EAI hexane) to provide 2.49 g (72.6%) of (S)-5-azido-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-6 as a white solid. LCMS-ESI (m/z) calculated for C11H10N4: 198.2; found 156.1 [M−N3]+, tR=3.65 min. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=7.6, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 0.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.59 (t, J=4.4 Hz, 1H), 3.08 (dt, J=18.0, 5.1 Hz, 1H), 2.99-2.83 (m, 1H), 2.15-1.96 (m, 3H), 2.00-1.81 (m, 1H). 13C NMR (101 MHz, DMSO) δ 141.05, 135.58, 133.47, 132.66, 126.58, 117.43, 113.21, 58.74, 28.28, 27.54, 18.27.
Reaction SMILES: C(O[CH:5]([C:22]1[N:23]=[CH:24][N:25]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]=1[CH3:27])[CH:6]1[C:20](=[O:21])[N:10]2[C:11]3[C:16]([C:17]([CH3:18])=[C:9]2[CH2:8][CH2:7]1)=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:20](=[O:21])[C:6](=[CH:5][C:22]3[N:23]=[CH:24][N:25]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]=3[CH3:27])[CH2:7][CH2:8][C:9]1=[C:17]2[CH3:18]
Reactant: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Yield: 87.7 %

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-2-chloro-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.40 g) in toluene (15 ml) was added 1.8-diazabicyclo[5.4.0]undec-7-ene (0.37 ml), and the mixture was refluxed for 2 hours. After being cooled, the solution was washed with water and brine, dried over sodium sulfate, evaporated, and triturated in diisopropyl ether, to give 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=3)=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH:69][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12](=[O:21])[C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:65][N:64]=3)=[CH:60][CH:61]=2)(=[O:54])=[O:55])[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 17 (Example 25) (0.134 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were used as-is for deprotection step. White solids (0.075 g, 24%).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:44]=1[C:55]([NH2:57])=[O:56]>C(Cl)Cl>[C:1]([C:3]1([C:6]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:44]=2[C:55]([NH2:57])=[O:56])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(=O)O)CC1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.75 g, 7 mmol) in DCM (40 mL) was added HATU (3.5 g, 10 mmol) and DIPEA (3.4 mL, 20 mmol). After stirring at room temperature for 1 h, 3-aminobiphenyl-2-carboxamide (from example 218: 1 g, 5 mmol) was added and the reaction mixture stirred for an additional 16 h. The reaction mixture was washed with water and the organic phase dried, filtered, concentrated under reduced pressure and purified by silica gel chromatography (60% ethyl acetate in hexanes) to provide 3-(1-cyanocyclopropanecarboxamido)biphenyl-2-carboxamide (0.75 g, 74% yield) as a white solid. LCMS Method T: retention time 1.53 min; [M+1]=306.2.