Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=[O:13].[Na+].NC(N)=O>OS(O)(=O)=O>[Cl:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2SO4 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaNO2 (2.5 M, 25 mL) was added dropwise such that the internal temperature remained at 5° C. Urea was added to the mixture for after stirring for 15 minutes to destroy excess NaNO2 (monitored by starch iodine test). CuSO4 (100-200 mg) was added and the mixture was heated to 90° C. until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3×). The combined organic fractions were extracted with 3N NaOH (3×). The combined aqueous layer was acidified with conc. HCl and the product was extracted with ethyl ether (3×). The organic fractions were washed with water, brine, and dried over MgSO4. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1/1) to afford 2-chloro-4-hydroxybenzoic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:51]1[C:53]2([CH2:58][CH2:57][N:56]([C:59]([NH:61][C@@H:62]([CH2:66][C:67]([F:70])([F:69])[CH3:68])[C:63](O)=[O:64])=[O:60])[CH2:55][CH2:54]2)[CH2:52]1>CN(C=O)C>[C:6]([C:3]1([NH:2][C:63]([C@@H:62]([NH:61][C:59]([N:56]2[CH2:55][CH2:54][C:53]3([CH2:51][CH2:52]3)[CH2:58][CH2:57]2)=[O:60])[CH2:66][C:67]([F:69])([F:70])[CH3:68])=[O:64])[CH2:5][CH2:4]1)#[N:7]
Reactant: N#CC1(N)CC1
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCC2(CC1)CC2)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CC1)CC2)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
142.3 mg of 1-aminocyclopropanecarbonitrile hydrochloride (1.2 mmol, 1.0 eq.), 163.3 mg of HOAt (1.0 eq.), 0.61 ml of DIPEA (3 eq.) and 456 mg of HATU (1.0 eq.) were added successively to a solution of 348.0 mg of (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoropentanoic acid (1.2 mmol) in 5 ml of DMF. The reaction mixture was stirred at RT for 24 h and then concentrated under reduced pressure. The residue was taken up in 10 ml of dichloromethane, washed with a little sat. NaHCO3 solution and then a little dilute HCl solution (pH=5), and dried over MgSO4. The residue thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product-containing fractions were combined and freeze-dried. In this way, N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-6-carboxamide was obtained as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[CH3:36][OH:37]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13]([O:37][CH3:36])=[N:14][CH:15]=1)=[O:9]
Reactant: CO
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Product: COc1ncc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
To a suspension of of 0.4 g (0.77 mmol) 2-methylsulfonyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml methanol 0.10 g (1.93 mmol) sodiummethanolat (95%) was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) to give 0.23 g (63%) 2-methoxy-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, m.p. 101.2-102°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[OH:21][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A solution of 4-bromobenzoic acid (4.02 g, 20.0 mmol) in tetrahydrofuran (100 mL) was purged with argon for 5 min. n-Butyllithium (16.0 mL of 2.5 M in hexanes, 40 mmol) was added dropwise at −78° C., resulting in a yellow thick syrup. The mixture was stirred at −78° C. for 30 min. Cyclopentanone (3.89 mL, 44.0 mmol) was added dropwise. The reaction was quenched immediately with saturated NH4Cl and allowed to warm to room temperature. The mixture was acidified with 1 N HCl to pH ˜3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue was suspended in hexanes, filtered, and the solid washed with additional hexanes. The solid was re-suspended in dichloromethane followed by hexanes. The resulting precipitate was filtered, washed with hexane and air dried to yield 4-(1-hydroxycyclopentyl)benzoic acid (1.25 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.93 (s, 1H), 1.93-1.71 (m, 8H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([CH:40]([CH3:46])[C:41]([O:43]CC)=[O:42])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.ClCCl>[F:21][C:20]([F:23])([F:22])[CH2:19][NH:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([C:34]4[CH:39]=[CH:38][C:37]([CH:40]([CH3:46])[C:41]([OH:43])=[O:42])=[CH:36][CH:35]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (250.0 mg, 0.6050 mmol) (from Example 1, step 4), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (280 mg, 0.91 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol, Aldrich, Cat. No. 379670) and sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (5 mL) and a few drops water was heated at 120° C. overnight under nitrogen. After the reaction was cooled to r.t., 1.0 M sodium hydroxide in water (2.4 mL,) was added to the above mixture. The reaction mixture was heated at 100° C. 2 h., then cooled to r.t. The reaction mixture was diluted with ethyl acetate, and extracted with 1N NaOH aqueous solution twice. The combined aqueous phases were acidified to pH˜2 with 6 M HCl aqueous solution, and then extracted with ethyl acetate twice. The combined organic phases (only the extracted portion with acidic aqueous solution) were washed with brine, dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product. LCMS (M+H)+: m/z=483.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][O:48][CH2:49][CH2:50][NH2:51].O>ClCCl>[CH3:47][O:48][CH2:49][CH2:50][NH:51][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24]
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCCNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 64 h
Yield: 25.8 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 409 μl (4.7 mmol) 2-Methoxy-ethylamine were added and the mixture was stirred for 24 h at room temperature. The reaction was poured into water and the precipitate filtered off. After drying of the residue in vacuo at 40° C., 91 mg (29%) of the title compound were isolated as a yellow solid. m.p. 254°-256° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1OC

Procedure:
The title compound was prepared from the product of Example 65A and 3,4-dimethoxyphenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 8.14 (d, 2 H), 7.19 (d, 1 H), 7.07 (d, 2 H), 6.93 (d, 1 H), 4.13 (s, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.81-3.30 (m, 7 H), 3.09-2.95 (m, 4 H), 2.34-2.18 (m, 3 H); LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.28 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]Br>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([Br:28])=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(C)cc3cnnc(OCc4ccccc4)c32)cc1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(Cn2c(C)c(Br)c3cnnc(OCc4ccccc4)c32)cc1
Yield: 78 %

Procedure:
1.8 g (5 mmol) of 7-benzyloxy-l-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine and 282 μl (5.5 mmol) of bromine are reacted in a total of 65 ml of dichloromethane and purified as described for Example 3a. Yield: 78%, m.p.: 149°-152° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)OC)cc2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)O)cc2)nc1Cl
Yield: 101.7 %

Procedure:
The same operation as in Example (91d) was performed using methyl 4-[(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101c) (0.13 g, 0.29 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (8 mL), to obtain 0.13 g of the title compound as a light brown solid (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][C:18]#[N:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:23][CH:22]=1.C(N(CC)CC)C.C>CC#N.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[C:29]4[C:21]([CH3:20])=[CH:22][NH:23][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:31][C@@H:32]2[CH3:36])=[N:17][C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 60.1 %

Procedure:
The cyanocarbamimidate from step A (9.48 g, 30 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from Example 1, step B (6.93 g, 30 mmol), and triethylamine (4.16 ml, 30 mmol) were combined in MeCN (250 ml) and heated to 85° C. for 6 hours. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (750 g SiO2, 0-7% MeOH:CH2Cl2) to give a yellow foam. This material was dissolved in MeOH and stirred with activated charcoal at 60° C. for 15 min. The mixture was filtered through celite, washing with copious amounts of MeOH and 10% MeOH:CH2Cl2, and concentrated under vacuum. The residue was purified again by flash chromatography (750 g SiO2, 0-7% MeOH:CH2Cl2). The resulting material was dissolved in MeOH, and water was added to crash out the product. The mixture was concentrated under vacuum, and the product was resuspended in water and lyophilized to give a hydrate of (S)—N-(3-bromophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (8.17 g, 57%, 1.25 eq. H2O based on CHN analysis) as an amorphous white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH2:32][O:33][CH3:34])#[N:2].CO.[OH-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH2:32][O:33][CH3:34])#[N:2]
Reactant: CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(COC)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 18 %

Procedure:
A mixture of 4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride, Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (209 mg, 0.73 mmol) and ethanol (4 mL) was stirred under argon at 80° C. for four hours. The mixture was cooled to room temperature and concentrated to give ethyl 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate as a yellow solid. The ester was suspended in tetrahydrofuran (4 mL), methanol (1 mL) and treated with 2.5 N sodium hydroxide (1 mL) at room temperature. After four hours the mixture was concentrated to half the original volume, treated with 6 N Hydrogen chloride (2 mL), dimethylsulfoxide (24 mL) and purified by reversed-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow/orange solid, 65 mg, 0.015 mmol, 18% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 7.80-7.87 (m, 2H), 7.60 (d, J=8.86 Hz, 1H), 7.35 (d, J=2.15 Hz, 1H), 7.18 (dd, J=8.86, 2.15 Hz, 1H), 4.92 (dd, J=9.80, 5.51 Hz, 1H), 4.50 (s, 2H), 3.59 (ddd, J=13.83, 9.40, 4.70 Hz, 1H), 3.36 (s, 3H), 3.06-3.15 (m, 1H), 2.82-2.96 (m, 1H), 2.19-2.29 (m, 1H), 2.00-2.13 (m, 1H), 1.65-1.89 (m, 2H), 1.14-1.54 (m, 7H). ES-MS m/z 430 (M+H)
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[Na].[CH3:24][CH:25]([OH:30])[CH2:26][C:27]#[C:28][CH3:29]>>[CH3:24][CH:25]([O:30][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22])[CH2:26][C:27]#[C:28][CH3:29]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Reactant: CC#CCC(C)O
Agent: [Na]
Product: CC#CCC(C)Oc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with the sodium derivative of 4-hexyn-2-ol to obtain 4-(1-methyl-3-pentyn-1-yloxy)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 402.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].C[CH2:42][O:43][C:44]([CH3:46])=O>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH:10]=[CH:11][C:46]([CH2:44][O:43][CH3:42])=[CH:13][CH:8]=2)=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 140 °C

Procedure:
A mixture of [(1S,2S)-1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (78 mg, 0.146 mmol), arylboronic acid (0.18 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (38 mg, 0.27 mmol) in CH3CN/H2O (3.5/0.5 mL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 576).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[Mg].II.[C:9]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])(=[O:13])/[CH:10]=[CH:11]/[CH3:12].Cl>C(OCC)C>[CH3:12][CH:11]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][C:9]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[O:13]
Reactant: CCCCBr
Reactant: C/C=C/C(=O)OC(C)CC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(C)CC(=O)OC(C)CC
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 388.1 %

Procedure:
Several drops of a solution of 4.9 g of n-butyl bromide in 126 ml of dry diethyl ether were added to a suspension of 10.53 g of magnesium and a trace amount of iodine in 80 ml of dry diethyl ether, and the mixture was stirred vigorously. The colour of the iodine disappeared upon slight heating, and the rest of the n-butyl bromide solution was then added dropwise at a rate sufficient to maintain a constant reflux of the reaction mixture. After addition of the n-butyl bromide solution the reaction mixture was heated to reflux for a further 15 minutes and was then cooled to 5° C. with an ice-water bath. Cuprous chloride (0.589 g) was divided into seven equal portions: one portion was added to the reaction mixture and then a solution of 23.9 g of sec-butyl crotonate in 120 ml of dry diethyl ether was added dropwise over 3 hours, during which time the six remaining portions of cuprous chloride were added at 30-minute intervals. After stirring the mixture at 5° C. for 15 minutes and then at room temperature for 1 hour, the reaction mixture was gradually poured into an ice-cooled mixture of 150 g of ice, 50 ml of concentrated hydrochloric acid and 60 ml of diethyl ether with vigorous stirring. The organic layer was separated from the reaction mixture obtained and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and then concentrated. The residue was purified by distillation under reduced pressure to give 27.8 g of the title compound having the following physical characteristics: