Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])([OH:6])=O.[C:15]1([C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]O1)=[O:16]>C(OCC)(=O)C>[CH:20]1[C:19]2[C:18]3[C:9](=[O:10])[C:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=4[C:4]=3[O:6][C:15](=[O:16])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C1OCc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Temperature: 65 °C
Yield: 85.5 %

Procedure:
Sodium methoxide (40 mL of a 4 M methanolic solution) was added to a solution of 2-carboxybenzaldehyde 1d (1.000 g, 7.455 mmol) and phthalide 2d (1.119 g, 7.455 mmol) in ethyl acetate (20 mL). The solution was heated at 65° C. for 18 h, concentrated, and acidified with coned HCl. The resulting mixture was diluted with benzene (125 mL), TsOH (100 mg) was added, and the solution was heated for 7 h at reflux in a flask affixed with a Dean-Stark trap. The solution was cooled to room temperature, concentrated, diluted with CHCl3 (150 mL), and washed with sat NaHCO3 (3×50 mL) and sat NaCl (50 mL). The organic layer was dried over sodium sulfate and concentrated to provide indenobenzopyran 4d as an orange solid (1.583 g, 86%): mp 258-259° C. (published mp 257° C.). 1H NMR (CDCl3) δ 8.40 (d, J=8.56 Hz, 1H), 8.32 (d, J=7.93 Hz, 1H), 7.84-7.79 (m, 1H), 7.61-7.39 (m, 5H). Additional details regarding the synthesis of compound 8 are found in Pailer et al., Monatsh Chem., 92:1037-47 (1961), the synthetic disclosure of which is incorporated herein by reference.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added isopropylsulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][O:15][CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)([CH2:11]2)[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:29][C:27]([F:28])([F:30])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=1)[CH2:16][O:15][CH2:14][C@@:10]12[CH2:11][CH:12]1[CH2:13][NH:8][C@H:9]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@@]2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(COC[C@@]23CC2CN[C@H]3c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A flask containing racemic Intermediate 24, one enantiomer being (1S,2S)-1-(3,5-bis-trifluoromethyl-benzyloxymethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.25 g, 0.49 mmol) and methylene chloride (10 mL) was immersed in a 0° C. bath. Trifluoroacetic acid (0.75 mL, 9.7 mmol) was added, and the reaction was stirred for 3 hours at room temperature. 20% NaOH solution was added cautiously and then saturated sodium bicarbonate solution was added until the pH=8. The phases were separated; the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.20 g, quantitative yield).
Reaction SMILES: C(O)(=O)/C=[CH:3]\[C:4](O)=[O:5].[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C@@H:17]3[C@H:22]([NH2:23])[CH2:21][CH2:20][CH2:19][N:18]3[C:12]=2[CH:11]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C@@H:17]3[C@H:22]([NH:23][C:4](=[O:5])[CH3:3])[CH2:21][CH2:20][CH2:19][N:18]3[C:12]=2[CH:11]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 131.3 %

Procedure:
trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine maleate (10 mg, 0.02 mmol), 50 μL of pyridine, and 25 μL of acetic anhydride in 1 mL of CH2Cl2 were stirred for 18 h at room temperature. The mixture was washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin1-yl)acetamide (9.0 mg, 65%). Data: (m/z)=343 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:18]=3)[CH:13]=2)=[C:8]([CH:11]=1)C=O)([CH3:3])[CH3:2].[Cl-].[CH3:26][O:27][CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:48](O[K])(C)(C)C>O1CCCC1>[CH:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][C:8]=3[CH:48]=[CH:28][O:27][CH3:26])[CH:13]=2)[CH:18]=1)([CH3:23])[CH3:24]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O[K]
Reactant: CC(C)c1ccc(-c2ccc3cc(C(C)C)ccc3c2)c(C=O)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=Cc1cc(C(C)C)ccc1-c1ccc2cc(C(C)C)ccc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Under an atmospheric argon gas flow, 5-isopropyl-2-(6-isopropyl-2-naphthyl)benzaldehyde in an amount of 4.4 g (14 mmol), (methoxymethyl)triphenylphosphoniumchloride in an amount of 5.1 g (15 mmol), t-butoxypotassium in an amount of 1.7 g (15 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into a three-necked flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was stirred under heating at the room temperature for one night. After the reaction terminated, adding water in an amount of 100 milliliter into the reacted solution, an organic layer was separated, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=10/90), and as a result, 4.3 g of an aimed compound (white crystal) was obtained (yield: 90%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C@H:18]([OH:34])[CH2:19][NH:20][C:21]([CH3:33])([CH3:32])[CH2:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)[CH:12]=[CH:11][C:10]=1[CH:35]([CH2:39][CH:40]=[CH2:41])[C:36]([OH:38])=[O:37].S(=O)(=O)(O)O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:2]([O:37][C:36](=[O:38])[CH:35]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:34])[CH2:19][NH:20][C:21]([CH3:33])([CH3:32])[CH2:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[C:14]([Cl:15])[C:9]=1[Cl:8])[CH2:39][CH:40]=[CH2:41])[CH3:3]
Reactant: C=CCC(C(=O)O)c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(C(=O)OCC)c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(Cl)c1Cl
Yield: 81 %

Procedure:
The acid of Example 19 (0.5 g) was dissolved in absolute ethanol (10 mL) and catalytic amount of conc.sulfuric acid was added. The reaction was stirred and heated to reflux overnight. Next day the reaction was concentrated and diluted with ethyl acetate and washed with 2.5N NaOH (2×20 mL), brine (20 mL) and dried over sodium sulfate. The crude mixture was purified by HPLC (eluted with CH3CN/H2O containing 0.1% TFA) to produce the desired product in 81% yield (0.43 g). MS(ES) m/e 536 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) : 8.35-8.48 (brs, 2H), 7.31-7.10 (m, 6H), 4.17-4.01 (m, 5H), 3.26-3.05 (m, 4H), 2.69-2.50 (m, 7H), 2.32 (t, 2H), 1.94 (d, 2H), 1.58-1.54 (t, 2H), 1.33 (s, 3H), 1.35 (s, 3H), 1.18 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[NH:5][C:4]=1[CH2:14][CH2:15][CH3:16])[CH3:2].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.Br>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4]=1[CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCCc1[nH]c2ccc(OC)cc2c1CC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCc1[nH]c2ccc(O)cc2c1CC
Yield: 98.8 %

Procedure:
3-Ethyl-5-methoxy-2-propyl indole (2.92 g) in 15 ml of hydrogen bromide acetic acid solution was heated at 100° C. for 4 hours. The cooled solution was poured into an aqueous sodium bicarbonate solution (100 ml) and ethyl acetate with stirring. The separated organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was chromatographed on silica gel using 30% ethyl acetate in n-hexanes as eluent to yield 3-ethyl-5-hydroxy-2-propyl indole (2.7 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH:39]=O>C(Cl)(Cl)Cl>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:39][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (1.51 g) was dissolved in chloroform (20 ml) and 3,4-dichlorobenzaldehyde (1.65 g), acetic acid (0.54 ml) and sodium triacetoxyborohydride (2.6 g) were added at room temperature. The mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture and the mixture was stirred and extracted three times with chloroform. The combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate (2.1 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:43])[NH:41]O)=[CH:36][CH:35]=1>CC#N>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:43]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[CH3:16])[O:15][N:41]=2)=[CH:36][CH:35]=1
Reactant: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Reactant: N=C(NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(c1nc(-c2ccc(F)cc2)no1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
To 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid (0.06 g, 0.212 mmol) in CH3CN (3 mL) was added CDI (0.034 g, 0.212 mmol). After 5 min, 4-fluoro-N-hydroxybenzenecarboximidamide (0.033 g, 0.212 mmol) was added. The resulting mixture was stirred at rt and then heated to 150° C. in a microwave for 20 min. Concentration was followed by column chromatography (EtOAc/hexanes) to obtain the desired product (0.0065 g, 8% yield): MS (APCI) m/z 401 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[NH:6][N:5]=[N:4]1)[CH3:2].[Br:9][CH2:10][CH2:11]Br.C1C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].O>[Br:9][CH2:10][CH2:11][O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[N:5][N:6]=1
Reactant: BrCCBr
Reactant: CCn1nn[nH]c1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CCn1nnnc1OCCBr
Yield: 40 %

Procedure:
A mixture of 57 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5one, 69 parts of 1,2-dibromoethane, 564 parts of silver carbonate and 900 parts of benzene was stirred and refluxed over weekend using a water separator (in the darkness). The whole was filtered off over Hyflo while hot, washed with trichloromethane and the filtrate was evaporated to dry. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The second fraction was collected and the eluent was evaporated, yielding 22.3 parts (40%) of 5-(2-bromoethoxy)-1-ethyl-1H-tetrazole (200).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[I:10].[OH-].[Na+]>C(O)(=O)C.O>[Cl:8][C:5]1[CH:6]=[C:7]([I:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1I
Reaction time: 2 h
Yield: 60.1 %

Procedure:
The solution of 2-amino-5-chloropyridine (10.0 g, 77.8 mmol) potassium acetate (7.63 g, 77.8 mmol) in 100 mL of acetic acid was heated to 85° C. and ClI (12.6 g, 77.8 mmol) in 50 mL of acetic acid was added dropwise. Reaction mixture was kept 2 h at this temperature, diluted with 1 L of water, neutralized with NaOH 1N solution to pH 7 and extracted with ethyl acetate (4×75 mL). Organic fraction were combined, washed with NaHCO3, filtered through celite and evaporated. The residue was subjected to column chromatography on silica (eluent—hexane/ethyl acetate 1/1) providing 5-chloro-3-iodopyridin-2-amine as yellow solid (11.9 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[CH:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]=1[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)=O>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1.[C:36]1([N:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]([CH:25]=[CH:13][C:3]3[C:4]([CH3:11])([CH3:12])[C:5]4[C:6]([N+:2]=3[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=4)=[C:28]2[C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1.[C:36]1([N:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]([CH:25]=[CH:13][C:3]3[C:4]([CH3:11])([CH3:12])[C:5]4[C:6]([N+:2]=3[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=4)=[C:28]2[C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=C1N(C)c2ncccc2C1(C)C
Reactant: O=Cc1c(-c2cccs2)n(-c2ccccc2)c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: C[N+]1=C(C=Cc2c(-c3cccs3)n(-c3ccccc3)c3ccccc23)C(C)(C)c2cccnc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 135 °C
Yield: 99.8 %

Procedure:
A solution of 1.73 g of 1,3,3-trimethyl-2-methylene-pyrrolo[2,3-b]pyridine in 3 ml of acetic anhydride was added to a solution of 1.72 g anhydrous 4-methylbenzenesulfonic acid in 5 ml of acetic anhydride, followed by 3.04 g of 3-formyl-1-phenyl-2-(2-thiophenyl)indole. The resulting mixture was stirred and heated at 135° C. for 1 minute, then was diluted with 60 ml of ethyl acetate and cooled to 0°-5° C. The solid product was collected by suction filtration, washed with ethyl acetate, and was combined with a second amount of solid obtained from concentration of the filtrate to give 6.26 g of damp crystals. Recrystallization from a mixture of 20 ml acetone, 2 ml methanol, and 40 ml ethyl acetate gave 3.88 g (61% theoretical) of dye 2 (absorbance maximum in methanol, 505 nm; absorptivity, 62,200), determined to be 95% pure by high-performance liquid chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14](=O)[NH:13][CH:12]=[C:11]([C:16]#[N:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O=P(Cl)(Cl)[Cl:20]>O1CCOCC1>[Cl:20][C:14]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[NH:8][C:7]=2[C:11]([C:16]#[N:17])=[CH:12][N:13]=1.[ClH:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c(=O)c2c1[nH]c1cc(Cl)ccc12
Solvent: C1COCCO1
Product: Cl
Product: N#Cc1cnc(Cl)c2c1[nH]c1cc(Cl)ccc12
Temperature: 93 °C
Reaction time: 5 h

Procedure:
To a slurry of 7-chloro-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-4-carbonitrile (24.95 g, 102 mmol) in dioxane (200 mL) was added POCl3 (79 g, 512 mmol) dropwise at 93° C. The reaction mixture was left to stir at 93° C. for 5 h, cooled to room temperature, and left to stir overnight. The reaction mixture was filtered, washed with MTBE, and dried to give the title compound as an HCl salt. 1H NMR (600 MHz, CD3SOCD3) δ 13.33 (s, 1H); 8.80 (s, 1H); 8.39 (d, 1H); 7.70 (d, 1H); 7.50 (dd, 1H). LRMS (APCI) calc'd for (C12H5Cl2N3) [M+H]+, 262.0. found 261.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1cccc(C(=N)N)c1
Product: COc1cccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=374.8 (M+), was prepared from 3-methoxybenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:33][N:4]1[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:6]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:2]([CH3:1])=[N:3]1
Reactant: Cc1n[nH]c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1
Temperature: 25 °C

Procedure:
A solution of 2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline (150 mg, 0.38 mmol) in anhydrous dimethylformamide (2 mL) was treated at 0° C. with sodium hydride dispersion (30 mg, 0.76 mmol of 60% NaH in oil) followed after 20 min with methyl iodide (54 mg, 0.38 mmol), and the stirred mixture was allowed to warm to RT overnight. Water was added and the mixture extracted with dichloromethane (3×20 mL). The organic layer was dried, concentrated, and the residue chromatographed on silica eluted with an ethyl acetate-hexane gradient containing 1% triethylamine, giving fractions containing two isomeric substances. The less polar isomer (18 mg) was thus obtained (methylation regiochemistry tentatively assigned by NMR). 1H NMR (CDCl3, 400 mHz) δ 8.41 (m, 2H), 8.21 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.3 Hz), 7.84 (d, 1H, J=9.5 Hz), 7.74 (ddd, 1H), 7.67 (d, 1H, J=8.3 Hz), 7.55 (ddd, 1H), 7.12 (m, 2H), 7.05 (m, 2H), 7.0 (m, 2H), 5.40 (s, 2H), 3.71 (s, 3H), 2.37 (s, 3H). HPLC-MS 4.81 min, m/e 407 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[O:17]([CH:24]1[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:31](OCC)C>>[O:17]([CH:24]1[CH2:25][CH2:26][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH:28]([CH3:31])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOCC
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Reactant: CN1CCC(Oc2ccccc2)CC1
Product: CC1CC(Oc2ccccc2)CCN1CC(=O)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-phenoxy-methyl-piperidine according to the method described in Example 142b. Melting Point: 172-175° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)=[O:10])[CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:18][CH:19]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CCCCC5)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of 2′-Chloro-5′-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid (103 mg), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (59 mg) and HBTU (148 mg) in dry DMF (10 ml) containing triethylamine (362 μl) was stirred at room temp for 18 h. Most of the DMF was evaporated and the residue diluted with water. The resulting solid was collected by filtration. This material was then purified by reverse phase Prep HPLC giving the title compound as a yellow solid (51 mg)
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:31][CH3:32])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:31]([N:12]1[C:13]2[CH:14]=[CH:15][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][C:18]=2[C:19]2[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]1=2)[CH3:32]
Reactant: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2

Procedure:
A mixture of 3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step I, 107 mg, 0.241 mmol) in methanol (20 mL, 1 drop concentrated hydrochloric acid) is treated with palladium on carbon (10%, 32 mg) and hydrogenated at 25 psi for 48 hr. The resulting mixture is filtered, rinsing with methanol and methylene chloride, and the filtrate is concentrated to a solid. The solid is purified via chromatography (10 g SG; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give the title compound, mp=224°, dec.; IR (drift) 2982, 2935, 2743, 1473, 1449, 1312, 25 1300, 1151, 1091, 819, 768, 728, 691, 647 and 623 cm−1; NMR (300 MHz, DMSO-d6) 8.09, 7.85-7.95, 7.45-7.65, 4.20, 2.95-3.25 and 1.15 δ; MS (EI) m/z 354 (M+), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS (FAB) calculated for C20H23N2O2S=355.1480, found 355.1488.