Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([Cl:35])=[O:18])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:30][CH:31]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)Cl)n21
Reaction time: 2 h

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (44 g, 95.8 mmol) was dissolved in CH2Cl2 (600 mL). To this solution was added oxalyl chloride (16.7 g) followed by DMF (0.3 mL). After 2 h, the volatiles were removed and the resultant residue was placed under high vacuum for 18 h to yield the title compound. The title compound was used without purification.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([OH:44])=O)=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:60][S:57]([CH:54]4[CH2:56][CH2:55]4)(=[O:59])=[O:58])=[O:44])=[C:40]([F:48])[CH:39]=3)[CH2:33][CH:32]3[CH2:34][CH:28]([CH2:29][CH:30]([CH2:31]3)[CH2:35]1)[CH2:27]2
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.13 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.5 Hz, 1H), 3.73 (s, 2H), 3.12-3.03 (m, 1H), 1.99 (s, 3H), 1.75-1.64 (m, 12H), 1.15-1.11 (m, 4H); MS (ES+) m/z 442.1, 444.1 (M+1); MS (ES−) m/z 440.2, 442.2 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)[CH:22]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: COc1cccc(/C=C/c2ccc([N+](=O)[O-])cc2)c1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 3-methoxybenzaldehyde yields the (E)-1-methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=255 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC(C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-(2-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)CC(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 99 %

Procedure:
To 66 g (1460 mmole) of anhydrous dimethylamine in 200 ml of methylene chloride and cooled to -30° C. was added a solution of 155 g (664 mmole) of 2-bromo-4'-chloroacetophenone in 200 ml of methylene chloride. After the addition was complete the reaction was allowed to warm to 20° C. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous sodium hydroxide, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo gives 130 g of the title compound, an oil.
Reaction SMILES: [F-:1].[Cs+].[C:3]1([S:9][CH2:10]Cl)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[C:3]1([S:9][CH2:10][F:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCSc1ccccc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CC#N
Product: FCSc1ccccc1
Yield: 58.5 %

Procedure:
Cesium fluoride (191.50 g, 2 eq) was added to a mixture of PEG400 (100 mL) and acetonitrile (600 mL). The mixture was stirred for a few minutes under an argon atmosphere and then acetonitrile (100 mL) was removed by distillation. Chloromethyl phenyl sulfide (100 g, 630.32 mmol) was added and the resulting mixture was stirred for 6 hours at a temperature between 80° C. and 85° C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by distillation to give 52.46 g (58.5%) of the desired product as slightly yellow oil (bp: 43° C. at 40 Pa).
Reaction SMILES: CI.[N:3]1[C:12]2[NH:11][C:10]3[CH:13]=[C:14]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[N:6]=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:19][C:18](=[O:20])[CH:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[N:6]=[CH:5][CH:4]=[N:3][C:12]=3[NH:11][C:10]=2[CH:13]=1)[OH:21]
Reactant: O=C(O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Yield: 64.7 %

Procedure:
150 mg of methyl iodide was added to a solution of 100 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyacetic acid in N,N-dimethylformamide (8 ml) in the presence of 260 mg of potassium carbonate. After purifying by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallizing from ethyl acetate/diisopropyl ether, 68 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=[C:11]([CH3:23])[CH:10]=1>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:9]1[C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=[C:11]([CH3:23])[CH:10]=1
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.75 g, 43.7 mmol) in THF (30 mL) a solution of 2-methoxyethanol (3.30 g, 43.7 mmol) in anhydrous THF (10 mL) was slowly added. The mixture was stirred at room temperature for 20 minutes and a solution of 4-chloro-2-methyl-[1,10]phenanthroline (2.00 g, 8.8 mmol) in anhydrous THF (20 mL) was added. The reaction mixture was refluxed for 18 hours and the solvent was removed in a rotary evaporator. The residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with hexane and purified by flash chromatography (SiO2, MeOH/DCM, 1:30) to afford the pure product as a light yellow solid (1.17 g, 50%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:34][C:9]2=[CH:10][N:11]([S:16]([C:19]3[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:21][C:20]=3[CH:31]([CH3:33])[CH3:32])(=[O:18])=[O:17])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:8]=32)[C:6]1=[O:35])(=[O:3])[CH3:2].[CH3:36][Mg]Br.[NH4+].[Cl-]>C1COCC1>[C:1]([NH:4][CH:5]1[CH2:34][C:9]2=[CH:10][N:11]([S:16]([C:19]3[C:20]([CH:31]([CH3:33])[CH3:32])=[CH:21][C:22]([CH:28]([CH3:29])[CH3:30])=[CH:23][C:24]=3[CH:25]([CH3:26])[CH3:27])(=[O:18])=[O:17])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:8]=32)[C:6]1([OH:35])[CH3:36])(=[O:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 4-acetylamino-3,4-dihydro-1-(2,4,6-triisopropylphenylsulfonyl)-benz[cd]indol-5-one (3.57 g, 7.0 mmol) in THF (70 ml) was added, at 40° C. in argon streams, a solution of 1M methyl magnesium bromide in THF (8 equivalents relative to ketone compound). The mixture was warmed to room temperature, and stirred for 4 hours. The reaction mixture was added to an ice-cooled saturated aqueous solution of NH4Cl and the mixture was subjected to extraction with ethyl acetate. The extract was washed with an aqueous saline solution and, then, dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (1:2) to afford 1.27 g (36%) of the title compound as an amorphous crystalline product. 1H-NMR(CDCl3, 200MHz) δ: 1.09(d,J=7 Hz,12H), 1.25(d,J=7 Hz,6H), 1.95(s,3H), 2.7-3.0(m,2H), 3.24(dd,J=16, 5 Hz,1H), 4.14(hept,J=7 Hz,2H), 4.54(m,1H), 5.3-5.5(br,1H), 7.1-7.4(m,6H) ppm. IR(KBr):3390, 2965, 1660 cm-1. Anal: Calcd for C29H38N2O4S.H2O: C 65.88%, H 7.63%, N 5.30% Found; C 66.13%, H 7.28%, N 5.69%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl 3-formylbenzoate (5.0 g, 30.5 mmol) in concentrated sulfuric acid (50 mL) was added N-bromosuccinimide (5.4 g, 30.5 mmol) in one portion at 0° C. After warming to room temperature, the reaction mixture was stirred for 2 days before being poured into 400 mL of ice/water. Once the ice had melted, the aqueous phase was extracted with DCM (2×400 mL). The combined organic phases were passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was purified via silica gel chromatography, eluting with 0-10% EtOAc in isohexane, to give the title compound as an oil that solidified upon standing (4.6 g, 63%). 1H NMR (400 MHz, CDCl3): δ 10.02 (s, 1H), 8.45 (t, J=1.5 Hz, 1H), 8.41 (t, J=1.7 Hz, 1H), 8.20 (t, J=1.7 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13](/[CH:21]=[CH:22]/[C:23](OCC)=[O:24])[CH:12]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:12]=1
Reactant: CCOC(=O)/C=C/c1cnc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC/C=C/c1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.0M, 31 ml) was added dropwise to a solution of ethyl (E)-3-(3-quinolinyl)acrylate (2.94 g) in CH2Cl2 (50 ml) at −78° C. and the mixture was stirred at −78° C. for 30 minutes. The reaction mixture was washed with saturated aqueous solution of sodium potassium tartrate and brine, dried and concentrated. The residue was crystallized from CH2Cl2-ethyl acetate to give the titled compound (1.31 g) as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[OH-].[Na+]>C(O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Yield: 89.3 %

Procedure:
The product of step A (510 mg, 1.16 mmol) was dissolved in ethanol (50 mL) and sodium hydroxide (6.5 mL of a 1N solution, 6.5 mmol) added. The solution was heated at reflux for 1.5 hours, diluted with water (45 mL), and the ethanol removed under vacuum. The solution was acidified to pH=3 with 1N HCl (˜7 mL) with stirring. The resulting solids were filtered, washed with water, and dried under vacuum to afford the product (308 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][C:21](=O)[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17].C1COCC1.[CH3:39][NH2:40].[OH-].[Na+]>O.CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([NH:40][CH3:39])[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17]
Reactant: CN
Reactant: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
A solution of the (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (120 mg, example 81.3) and 12 ml of THF saturated with methylamine was treated at 5° C. with 3.5 ml of AcOH until pH=6 and the mixture was warmed to 22° C. After 1.5 h, the mixture was treated with 24 mg of Na(CN)BH3 and stirring was continued for 2.5 h. The mixture was diluted with 5 ml of water, the pH was adjusted to 14 using 3 N NaOH and the solution was extracted with THF. The organic layer was dried and evaporated to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methylamino-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless foam. MS 504.0 ([M+H]+)
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)Cl>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47, 20 mg, 0.066 mmol), 6-chloro-N-methylnicotinamide (Example 71A, 11 mg, 0.066 mmol) and K2CO3 (27 mg, 0.20 mmol) in N,N-dimethylformamide (0.25 mL) was heated to 100° C. for 1 hour, cooled, diluted with CH2Cl2, filtered, and concentrated. The residue was purified by HPLC as described in Example 66. The product was further purified by chromatography on silica gel eluting with a gradient of 2 to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44-1.53 (m, 2H), 1.59-1.67 (m, 4H), 1.94-2.10 (m, 1H), 2.24-2.34 (m, 1H), 2.39-2.57 (m, 4H), 2.95-3.06 (m, 1H), 3.01 (d, J=4.7 Hz, 3H), 3.43 (t, J=9.3 Hz, 1H), 3.48-3.60 (m, 1H), 3.70-3.89 (m, 2H), 6.09-6.18 (m, 1H), 6.92 (dd, J=8.5, 0.7 Hz, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.12 (dd, J=8.6, 2.5 Hz, 1H), 8.53 (dd, J=2.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: C[CH2:2][N:3](CC)[CH2:4]C.[CH3:8][N:9]1[C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][C:21]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31]([OH:33])=O)=[O:28])[CH2:23][CH2:22]3)[C:12]=2[CH:11]=[N:10]1.Cl.CNC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[C:27]([N:24]1[CH2:25][CH2:26][C:21]2([C:12]3[CH:11]=[N:10][N:9]([CH3:8])[C:13]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20]2)[CH2:22][CH2:23]1)=[O:28]
Reactant: CCN(CC)CC
Reactant: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2ccccc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
Et3N (170 μL, 1.2 mmol) was added to a mixture of 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoic acid (100 mg, 0.25 mmol), N-methylmethanamine hydrochloride (30 mg, 0.37 mmol), EDCI (48 mg, 0.25 mmol), and CH2Cl2 (1.5 mL) at ambient temperature. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 and was washed with 1N HCl. The layers were separated and the organic layer was washed with 1N NaOH, and then brine before it was dried over sodium sulfate and was concentrated in vacuo to give N,N-dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamide (38 mg) as a white solid. ESI-MS m/z calc. 430.2, found 431.3 (M+1)+; Retention time: 2.24 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H), 7.30-7.21 (m, 1H), 7.13-7.00 (m, 2H), 4.52 (d, J=13.5 Hz, 1H), 4.19 (s, 3H), 3.74-3.51 (m, 2H), 3.31 (t, J=11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24-2.02 (m, J=13.9 Hz, 2H), 2.02-1.76 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH:19](=[N+:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(c1ccccc1)=[N+]1CCCCC1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [Cl-]
Product: c1ccc(COc2ccc3[nH]cc(C(c4ccccc4)N4CCCCC4)c3c2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and 1-benzylidene-piperidinium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C(OCC)(=O)C.O>C(Cl)Cl>[CH3:15][NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CN=C=O
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(NC(=O)NC)cc1
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-aminocinnamate (150 mg) in methylene chloride were added methyl isocyanate (0.06 ml) under nitrogen atmosphere at ambient temperature, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water twice, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-(3-methylureido)cinnamate (136 mg).
Reaction SMILES: [OH:1][C:2]([CH3:15])([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[CH:16]1([N:22]=[C:23]=S)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH:16]1([NH:22][C:23]2[O:1][C:2]([CH3:15])([CH3:14])[CH:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:4](=[O:5])(=[O:6])[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(O)C(c1ccccc1)S(N)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1ccccc1
Reaction time: 0.33 h
Yield: 20.9 %

Procedure:
A solution of 150 mg of 2-hydroxy-2-methyl-1-phenylpropane-1-sulfonamide and 97 mg of cyclohexyl isothiocyanate in 1.5 ml of NMP was admixed with 0.20 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring for 20 minutes, 71 mg of N-bromosuccinimide were added and the mixture was stirred at room temperature for a further 15 minutes. The reaction solution was admixed with 50 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were freed of the organic solvent under reduced pressure. The aqueous residue was extracted three times with dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was dissolved in a mixture of acetonitrile and water and lyophilized. This gave the product (46 mg) with a molecular weight of 336.4 g/mol (C17H24N2O3S); MS (ESI): m/e=337 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@@H:9]([OH:30])[CH2:10][C@H:11]([C:14](N1[C@H]2C3C=CC=CC=3C[C@H]2OC1(C)C)=[O:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH2:12][CH3:13])[C:14](=[O:15])[O:30]1)[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C[C@@H]([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1S,2S,4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid tert-butyl ester (VIII, 60 mg) was dissolved in 5:1 toluene/CH2Cl2 (3 mL), and p-toluenesulfonic acid monohydrate (23 mg) was added. This was stirred at rt for 18 h. The mixture was then filtered, and partitioned between half-saturated NaHCO3 (3 mL) and 1:1 EtOAc/hexanes (2×3 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue afforded desired product as a solid: MH+370.2.