Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)[O:9][C:4]=2[C:3]=1[CH2:22][CH2:23][CH3:24].Cl.[CH2:26](O)[CH3:27]>C(OCC)(=O)C>[OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:26][CH3:27])=[O:15])=[CH:12][CH:11]=3)[O:9][C:4]=2[C:3]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCO
Reactant: CCCc1c(O)ccc2c(=O)cc(-c3ccc(C(=O)O)cc3)oc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c(=O)cc(-c3ccc(C(=O)OCC)cc3)oc12

Procedure:
The solid acid product of step (a) (5.0g) was suspended in dry ethanol and the mixture saturated with hydrogen chloride, following which dissolution of the solid occurred. The solution was refluxed for 1 hour and evaporated to dryness. The solid obtained was dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate, filtered and evaporated to leave a pink solid. The solid was recrystallised from aqueous ethanol to give 3.5g of ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoate, melting point 225°-6°.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:19][CH:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a mixture of cyanuric chloride (5.15 g, 27.9 mmol), potassium carbonate (3.98 g, 28.8 mmol) and 18-crown-6 (158 mg, 0.60 mmol) in toluene (40 ml), cooled in an ice bath, was added a solution of 4-chloroaniline (3.61 g, 28.3 mmol) in toluene (20 ml) over 15 minutes. After stirring at room temperature for 20 hours, the mixture was treated with ethyl acetate (60 ml) and filtered through a pad of celite under suction. The filtrate was concentrated under vacuum and recrystallized (chloroform) to give (4-chloro-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (4.06 g, 53% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.23 (1H, s), 7.62 (2H, d, J=9 Hz), 7.47(2H, d, J=9 Hz). 13C NMR (d6-DMSO) δ 169.5, 168.5, 163.6, 135.7, 128.6, 122.5, ESMS m/z 273 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1
Yield: 54 %

Procedure:
A solution of 3,5-dinitroaniline (10 g, 54.644 mmol) and 2,5-dimethoxytetrahydrofuran (18.05 g, 136.61 mmol, 2.5 eq.) in acetic acid (122 ml) was heated to 100° C. for 16 h. Completion of reaction was monitored by TLC. Then the mixture was brought to RT and poured into ice-cold water. The precipitate was filtered, washed with water (150 ml) and dried to give the product in 54% yield (8.2 g). LC-MS (ESI): Calculated mass: 233.18; Observed mass: 233.04 [M+H]+ (rt: 1.667 min).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][O:7][CH2:8][CH2:9][OH:10].S(=O)(=O)(O)O>CCOCC>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][O:10][CH2:9][CH2:8][O:7][CH3:6]
Reactant: ClCC1CO1
Reactant: COCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COCCOCC(O)CCl
Yield: 43929.9 %

Procedure:
To 25 g (0.27 mmol) of epichlorohydrin, 20.8 g (0.27 mmol) of methylcellosolve and 0.1 ml of conc. sulfuric acid were added and reacted for 10 hours at 100° C. After the reaction, 500 ml of ether was added and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ether phase was dried on magnesium sulfate, filtered and concentrated to give 20 g of 1-chloro-2-hydroxy-3-(2'-methoxyethoxy)propane. 1H-NMR (CDCl3): δ=3.40 (3H, s, --OCH3), 3.45-3.82 (9H, m, H1, H3, H1', H2', --OH), 3.84-4.18 (1H, m, H2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1COCC1.S(Cl)(Cl)=O.[CH3:24][N:25](C=O)[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloroquinoline-4-carboxylic acid (5.0 g) and THF (48 mL) was added a small amount of DMF, followed by addition of thionyl chloride (1.8 mL) with ice cooling. The mixture was stirred at room temperature for 1 h and then at 60° C. for 1 h. The mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was diluted with chloroform (30 mL). The mixture was ice-cooled, followed by addition of 50% aqueous dimethyl amine (20 mL), and the mixture was stirred for 10 min. 1 M aqueous sodium hydroxide was added, the mixture was extracted with chloroform, the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain the title compound (4.6 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]1[CH2:37][O:36][C:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C@H:20]4[C@H:30]([C:31](=[O:35])[CH2:32]3)[C@:28]3([CH3:29])[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)([CH3:15])[O:13]1>>[CH2:37]1[CH2:12][O:13][C:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C@H:20]4[C@H:30]([C:31](=[O:35])[CH2:32]3)[C@:28]3([CH3:29])[C@H:23]([CH2:24][C@@H:25]5[O:6][C@@H:26]5[CH2:27]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)([CH3:15])[O:36]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Yield: 86.9 %

Procedure:
85%-m-Chloroperoxybenzoic acid (14.74 g) was added to a stirred solution of 20,20-ethylenedioxy-5α-pregn-2-en-11-one (26.0 g) at 20° to 25° during 15 minutes. After 45 minutes the solution was washed with 5% sodium hydrogen carbonate solution (2×300 ml) and water (300 ml). Evaporation of the solvent and crystallisation of the residue from 1% pyridine in methanol (300 ml) gave the title compound (23.6 g) m.p. 159°-160°.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:12][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(Nc2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cupric acetate (2.1 mmol) and pyridine (0.25 ml) were added to a vigorously stirred solution of 3-methoxyaniline (1 mmol) and 3-methoxyphenylboronic acid (2 mmol) in dry methylene chloride (3.5 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 72 h (the progress of the reaction was monitored by TLC). N-(3-Methoxyphenyl)-3-methoxyaniline (3c) was isolated by direct flash chromatography of the crude reaction mixture following preabsorption on silica gel. Yield (3c): 25%; EI-MS 229 (M+) [Lit.: Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135-9142].
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[I:16]I>CN(C1C=CN=CC=1)C.C1COCC1.O>[F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([I:16])=[CH:3]1
Reactant: II
Reactant: O=C1C=CC(F)(F)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(F)(F)C=C1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of the 4,4-difluorocyclohex-2-en-1-one (1.0 g, 7.57 mmol) prepared in Example 88b in a THF-water mixed solvent (1:1; 20 mL), potassium carbonate (1.30 g, 9.41 mmol), iodine (2.9 g, 11.4 mmol) and DMAP (0.56 g, 4.58 mmol) were added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was subjected to extraction with ethyl acetate (20 mL). The thus obtained organic layer was washed with an aqueous sodium thiosulfate solution (20 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (1.46 g, 75%) as a light brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH:19]3[CH2:21][CH2:20]3)=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example 2.6) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 500.3 (M+H+; 100%)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CO>C1COCC1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH2:16][NH2:17])=[CH:3][CH:2]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1cccc2[nH]c3ccccc3c12
Temperature: 85 °C
Yield: 52.9 %

Procedure:
To a mixture of (9H-carbazol-4-yloxy)acetonitrile (1.13 g, 5.1 mmol) in dry THF (50 mL) is added borane-methyl sulfide complex (1.4 mL, 15.3 mmol). The mixture is heated at 85° C. for 6 h. Methanol is added slowly until gas evolution ceased. The solvents are removed under reduced pressure. Methanol (20 mL) is added then removed under reduced pressure. Methanol (50 mL) and concentrated hydrochloric acid are added and the mixture heated at 65° C. overnight. The mixture is neutralized with saturated potassium carbonate and partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (200 mL), using CH3OH/CH2Cl2 (4/96) gave 0.61 g (53%) of the title compound; IR (drift) 3082, 1608, 1585, 1456, 1443, 1346, 1336, 1303, 1252, 1222, 1098, 911, 782, 750, 719 cm−1. 1H NMR (DMSO-d6) δ3.05, 4.13, 6.65, 7.03, 7.12, 7.24, 7.31, 7.41, 8.12; Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 73.90; H, 6.32; N, 12.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)CC(C)OB([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:32]([F:35])([F:34])[C:30]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1)=[CH2:31]
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(c1ccc(NC(=O)OC(C)(C)C)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a mixture of tert-butyl 4-bromophenylcarbamate (1.67 g, 6.14 mmol), potassium carbonate (3.38 g, 24.46 mmol), and tetrakis(triphenylphosphine)palladium (365 mg, 0.316 mmol), was added 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (1.64 g, 7.39 mmol), and degassed 1,2-dimethoxyethane (40 mL) and water (20 mL). The mixture for refluxed for 2 hours, cooled to ambient temperature, added more of 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (475 mg, 2.14 mmol) and tetrakis(triphenylphosphine)palladium-(189 mg, 0.164 mmol), and refluxed for 5 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water (200 mL), extracted twice with ethyl acetate (200 mL), washed with brine, dried (Na2SO4) and concentrated to an orange oil. The residue was purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; eluted with 0-15% ethyl acetate in hexane at 30 mL/min) to provide the title compound (1.223 g, 4.26 mmol, 69.4% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.53 (s, 1H), 7.52 (d, J=8.8, 2H), 7.40 (d, J=8.4, 2H), 6.03-5.99 (m, 1H), 5.97-5.94 (m, 1H), 1.48 (s, 9H); MS (DCI/NH3) m/e 305 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:16][CH:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:2]=2)[CH:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Cc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 52.7 %

Procedure:
Ethyl 3-(2-cyano-4-pyridyl)-2-methylpropionate (0.50 g, 2.3 mmol) and methyl thiosalicylate (0.96 g, 5.7 mmol) were dissolved in toluene (2 ml), and triethylamine (11.0 ml, 5.7 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs and combined with isopropyl ether to precipitate crystals, which were collected by filtration and recrystallized from ethyl acetate to give the titled compound (0.43 g, 53%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=1>CN(C)C=O.O>[Cl:1][C:2]1[N:6]([CH2:14][C:15]2[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Combine 2-chlorobenzimidazole (10.0 g, 66 mmol), and dimethylformamide (100 mL). Add portionwise sodium hydride (1.63 g, 68 mmol). After the evolution of gas ceases, add a solution of ethyl 2-chloromethyl-5-furoate (12.45 g, 0.66 mmol) in dimethylformamide (20 mL). After 18 hours, dilute the reaction mixture with water and extract four times with diethyl ether. Combine the organic layers and extract with water and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue eluting with 5% methanol/0.2% concentrated aqueous ammonia solution/dichloromethane to give 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:57]=[CH:56][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[C:22]([C:29](=[O:48])[N:30]([C:39]6[S:40][C:41]7[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=7[N:43]=6)COCC[Si](C)(C)C)[CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[N:16][C:15]=3[C:49]([O:51]C(C)(C)C)=[O:50])=[CH:8][CH:7]=2)[CH:3]=[N:2]1.Cl>C(Cl)Cl.CCOCC>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:57]=[CH:56][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[C:22]([C:29](=[O:48])[NH:30][C:39]6[S:40][C:41]7[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=7[N:43]=6)[CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[N:16][C:15]=3[C:49]([OH:51])=[O:50])=[CH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2cn[nH]c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4cn[nH]c4)cc3)s1)CC2

Procedure:
Compound 73A (30 mg) in DCM (1 ml) was treated with HCl 2 N in ether (5 ml) for 2 days. The precipitate was collected and dried to give the title compound 73: 1H NMR (400 MHz, DMSO-D6) δ ppm 8.09 (2H, s), 8.02 (1H, d), 7.79 (1H, d), 7.68 (1H, d), 7.51 (2H, d), 7.44-7.48 (2H, m), 7.33-7.42 (2H, m), 6.91 (2H, d), 4.87 (2H, s), 3.99 (2H, t), 3.75 (2H, t), 3.19 (2H, t), 3.04 (2H, t); LCMS (APCI) m/e 637 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]2=[NH:16])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.O=[C:18]([CH3:22])[C:19](=[S:21])[NH2:20]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:20][C:19](=[S:21])[C:18]([CH3:22])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N=C1c2cc(Br)ccc2CC12CCOCC2
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-imine (Example 25 Step 2, 235 mg, 0.84 mmol) and 2-oxopropanethioamide (Intermediate 2, 173 mg, 1.68 mmol) were taken up in anhydrous MeOH (5 mL) and the resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 3 h. When cooled to r.t. the mixture was concentrated and purified on a silica gel column eluted with 0-50% EtOAc in heptane to give 385 mg (95% yield) of the title compound; 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.40 (br. s, 1 H), 7.53 (dd, 1 H), 7.36 (d, 1 H), 7.03 (d, 1 H), 3.71 (td, 2 H), 3.44 (m, 2 H), 3.15 (m, 2 H), 2.29 (s, 3 H), 1.64 (s, 1 H), 1.55 (s, 1 H), 1.27 (m, 2 H); MS (ES+) m/z 365 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:26][CH:25]=1)[CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2c[nH]c3ccccc23)cc1)Cc1nc2ccccc2[nH]1

Procedure:
Using General Procedure B: 1H-Indole-3-carbaldehyde (73 mg, 0.50 mmol) and N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) were stirred at 40° C. in MeOH (5 mL) for 4 hours. NaBH4 (38 mg, 1.0 mmol) was added and the resultant mixture stirred at room temperature for an additional 15 minutes. Purification of the crude white foam by column chromatography on silica gel (200:1:1—EtOAc:MeOH:NH4OH) afforded AMD9673 (80 mg, 31%) as a white foam. 1H NMR (CDCl3) δ 1.59–1.75 (m, 1H), 1.81–2.09 (m, 2H), 2.16–2.30 (m, 1H), 2.64–2.76 (m, 1H), 2.76–2.91 (m, 1H), 3.69 (s, 2H), 3.78 (s, 2H), 3.92–3.98 (m, 3H), 4.04–4.09 (m, 1H), 4.15 (d, 1H, J=16.5 Hz), 7.02–7.07 (m, 2H), 7.11–7.21 (m, 6H), 7.25–7.34 (m, 3H), 7.41 (d, 1H, J=7.2 Hz), 7.54–7.57 (m, 3H), 8.68 (d, 1H, J=3.9 Hz), 8.75 (br s, 1H); 13C NMR (CDCl3) δ 21.74, 23.88, 29.60, 44.05, 48.89, 52.95, 54.06, 60.72, 111.68, 113.70, 119.08, 119.77, 121.97, 122.30, 122.66, 123.71, 127.40, 128.84, 129.07, 135.15, 136.70, 137.66, 138.60 (2 carbons), 147.27, 156.70, 157.79. ES-MS m/z 532.4 (M-C9H8N). Anal. Calcd. for C34H34N6.0.7H2O.0.2CH2Cl2: C, 73.84; H, 6.49; N, 15.11. Found: C, 73.95; H, 6.60; N, 14.81.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]([C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].Cl[C:20]1[N:28]2[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:30][O:31][C:26]3=[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[C:38]2[C:39]([CH3:44])=[N:40][O:41][C:42]=2[CH3:43])[N:21]=1>CN1CCCC1=O.CO>[CH3:44][C:39]1[C:38]([C:25]2[C:26]3[O:31][CH2:30][C@H:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[N:28]4[C:20]([N:16]5[CH2:17][CH2:18][C@@H:14]([C:12]([NH:11][CH:8]([CH3:10])[CH3:9])=[O:13])[CH2:15]5)=[N:21][C:22]([C:27]=34)=[CH:23][CH:24]=2)=[C:42]([CH3:43])[O:41][N:40]=1
Reactant: CC(C)NC(=O)[C@@H]1CCNC1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](C(=O)NC(C)C)C3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 120 °C
Yield: 10.2 %

Procedure:
Triethylamine (110 μL, 0.79 mmol) and (3R)—N-isopropylpyrrolidine-3-carboxamide (120 mg, 0.74 mmol) were added to a solution of (4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (66.0 mg, 0.18 mmol) in N-methylpyrrolidinone (1.5 mL), and the resulting mixture was heated in a microwave at 120° C. for 5 min. The mixture was diluted with methanol and purified twice by preparative LCMS using pH 10 buffer to give the title compound, (8.9 mg, 10%). LCMS calc. for C27H31N6O3 (M+H)+: m/z=487.2. found: 487.3. 1H NMR (500 MHz, DMSO) δ 8.54 (dd, J=4.8, 0.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.72 (td, J=7.7, 1.8 Hz, 1H), 7.29 (dd, J=6.8, 4.9 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.60 (d, J=7.9 Hz, 1H), 6.09 (t, 1H), 4.82 (dd, J=11.4, 1.3 Hz, 1H), 4.53 (dd, J=11.5, 2.8 Hz, 1H), 3.85-3.71 (m, 3H), 3.43 (dd, J=9.6, 7.6 Hz, 1H), 3.39-3.32 (m, 1H), 2.90 (p, J=7.8 Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H), 2.00-1.89 (m, 2H), 1.01 (dd, J=10.1, 6.6 Hz, 6H).