Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].O=[C:6]1[CH:11]([C:12]([O:14]CC)=O)[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1.[O:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)=[CH:27][N:26]=[CH:25]1>C(O)C>[OH:14][C:12]1[C:11]2[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:7][C:6]=2[N:38]=[C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([C:28]3[O:24][CH:25]=[N:26][CH:27]=3)=[CH:30][CH:31]=2)[N:37]=1
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(O)nc(Nc3ccc(-c4cnco4)cc3)nc2C1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
Sodium ethoxide (0.476 g, 7.00 mmol) was added to 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (1.899 g, 7.00 mmol, Example 1d) and 1-(4-(oxazol-5-yl)phenyl)guanidine (1.415 g, 7.00 mmol, Example 1e) in ethanol (10 mL). The reaction vial was heated a microwave reactor at 100° C. for 15 minutes. The suspension was diluted with ethanol (5 ml) and the precipitated crude product was filtered off and washed with cold ethanol to give tert-butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.200 g, 41.9%). No further purification. MS (ESI+)/(ESI−) m/z 410/408
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH3:19])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]>CO>[CH3:19][CH:17]([OH:18])[C:15]1[O:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Sodium borohydride (9.0 g, 0.34 mole) was added in portions to a stirred mixture of 55 g (0.24 mole) of methyl 5-(p-nitrophenyl)-2-furyl ketone in 700 ml of methanol at 20°-25° over 45 minutes. The mixture was stirred at ambient temperature for 4 hours and allowed to stand overnight. Some insoluble material was removed by filtration and discarded. The filtrate was poured into a mixture of ice and water (3 liters) and made acidific with 5% aqueous HCl. The brown oil which was deposited solidified on standing and was collected by filtration to give 56 g (100%) of title compound. Recrystallization from a cyclohexane-benzene mixture gave an analytical sample, m.p. 69.5°-70.5°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:35].[H][H]>[Pd].CO>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[NH:5][C:6](=[O:29])[C@@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 0.33 h

Procedure:
Nα -Benzyloxycarbonyl-D-tryptophyl-L-leucine methyl ester, 2.75 g., and 2.65 ml. of 2.23 N hydrogen chloride are dissolved in 100 ml. of methanol followed by the addition of 300 mg. of 10% palladium-on-carbon. The reaction is stirred under a hydrogen atmosphere with hydrogen bubbling through the mixture for seventy minutes. Thin layer chromatography indicates the reaction to be complete in about 20 minutes. The mixture is filtered and the solvent evaporated. The residue is dried under reduced pressure, 2.21 g. of D-tryptophyl-L-leucine methyl ester hydrochloride, [α]D23 -73° (c 1.02, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:45]2
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(Cl)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
(4-Chloro-phenyl)-phenylamino-acetic acid (I256) (1.22 g, 4.97 mmol), HOBT (0.99 g, 6.46 mmol) and DCC (1.33 g, 6.46 mmol) are dissolved in THF (250 mL). The reaction is stirred for 15 minutes and then (R)-quinuclidin-3-ol (1.26 g, 9.93 mmol) is added. The reaction is stirred at RT for 4 days. The solvent is evaporated and the residue is taken up with EtOAc. The insoluble is filtered off, the solution is washed with 1M K2CO3 and brine. The organic phase is dried (Na2SO4), filtered and evaporated to dryness. The crude is purified by flash chromatography (DCM/MeOH=98/2 to 90/10) to afford compound C259 as a yellow solid (462 mg, 25% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:8][N:7]1[C:3]([C:1]#[C:2][C:17]2[CH:16]=[C:15]([NH:20][C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[C:24]([C:36]([F:39])([F:37])[F:38])[CH:23]=3)=[O:40])[CH:14]=[CH:13][C:18]=2[CH3:19])=[CH:4][N:5]=[C:6]1[C:9]([NH2:11])=[O:10]
Reactant: C#Cc1cnc(C(N)=O)n1C
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc(C(N)=O)n1C

Procedure:
The title compound can be synthesized from 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 2. 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide is prepared as in Example 2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](Br)=[CH:7][C:5]=2[N:6]=1.CN(C)CCN(C)C.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCC>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([B:25]([OH:30])[OH:26])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Br)ccc2s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Nc1nc2cc(B(O)O)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 63 (459.1 mg) in anhydrous THF (30 ml) was added with N,N,N′,N′-tetramethylethylenediamine (1.51 ml, WAKO), cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of t-butyllithium in pentane (7.06 ml) and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (2.77 ml), stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (7.5 mL) and extracted with diethyl ether (50 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 2-amino-5-benzothiazoleboronic acid. According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 12 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=2:1), the above compound was reacted with Intermediate 3 (344 mg), 2 M aqueous sodium carbonate (4.5 ml) and (Ph3P)4Pd (179 mg) and treated to obtain the title compound (Compound No. 284, 76 mg).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9](CC#C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:37]C1C=CC(S)=CC=1>CN(C=O)C.C(OCC)(=O)C>[ClH:1].[F:37][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:6]3([C:4]([NH:3][OH:2])=[O:5])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(S)cc1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Sc3ccc(F)cc3)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Part A: To a solution of the sulfone of Example 9, part D (6.0 g, 14.4 mmol) in DMF (30 mL) were added potassium carbonate (2.39 mg, 17.3 mmol) and 4-fluorothiophenol (3.0 mL, 28.1 mmol), and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate and washed with 1N NaOH and saturated NaCl, and then dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as a solid (6.6 g, 87%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>CN1C(=O)CCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCC1CCOCC1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2c(NCC3CCOCC3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 120 °C
Yield: 54.1 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5 ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4-yl)methanamine (0.82 g, 7.12 mmol) and the mixture was heated at 120° C. for 3 h, then cooled and the brown solution loaded onto a 70 g SCX-2 cartridge, the column washed with methanol (200 ml) and then eluted with 2M methanolic ammonia (100 ml) and methanol (100 ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30 ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide (1.58 g, 3.85 mmol, 54.1% yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 411
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([C@@H:16]1[O:18][CH2:17]1)[Cl:15]>C1(C)C=CC=CC=1>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[C:10](=[O:13])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12]1
Reactant: ClC[C@H]1CO1
Reactant: Oc1cc(-c2ccc(Cl)cc2)on1
Solvent: Cc1ccccc1
Product: O=C1C[C@H](c2ccc(Cl)cc2)ON1CC(O)CCl
Reaction time: 20 h
Yield: 72.3 %

Procedure:
5-(p-Chlorophenyl)-3-hydroxyisoxazole (80.0 g) was slowly added at 80° C. to a toluene solution (80 ml) of (R)-(-)epichlorohydrin (50.0 g), and the reaction solution was stirred for 20 hours at 80°-85° C. After cooling the reaction solution, the deposited crystalline precipitate was washed with cold toluene (200 ml) to give 85.8 g of the desired product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5]>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2ccc(C(=O)O)cc2s1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(CO)cc2s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester (6.40 g, 25.57 mmol) in 250 mL of anhydrous THF at 0° C. was slowly added BH3 (1.5 M in THF, 80.0 mL, 120 mmol). The resulting mixture was allowed to stir at 0° C. for 30 min and at rt overnight. After cooling to 0° C., the reaction mixture was quenched with 1N HCl (30 mL). Additional 120 mL of water was added and THF was removed in vacuo. The solid formed was filtered and washed with 2×20 mL of water. After drying, 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. 1H NMR (CDCl3, 200 MHz) δ 8.00 (s, 1H), 7.88-7.76 (m, 2H), 7.36 (d, J=9.4 Hz, 1H), 4.80 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 2.00 (brs, 1H), 1.39 (t, J=7.0 Hz, 3H). MS (EI): cal'd 237.0 (MH+), exp 237.1 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([NH:12][CH:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])=[O:11].[Br:23][C:24]1[CH:28]=[C:27]([C:29](OCCCCC)=[O:30])[N:26]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.Cl>CS(C)=O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:7][C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10](=[O:11])[NH:12][CH:13]([CH:15]2[CH2:17][CH2:16]2)[CH3:14])=[O:30])[N:26]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1
Reactant: CCCCCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 13.9 %

Procedure:
0.11 g potassium tert-butoxide was added to a mixed solution comprising 0.19 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.30 g of pentyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and 3 ml of dimethyl sulfoxide, followed by reaction at room temperature for 45 minutes. The reaction liquid was slowly added to 40 ml of diluted hydrochloric acid. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7.5/2.5) to obtain 0.058 g of the desired product (melting point: 231 to 233° C.) in the form of white crystals.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[N:19]=[C:20](O)[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:41])=O>C([O-])(O)=O.[Na+]>[CH2:1]([O:8][CH:9]([C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[N:19]=[C:20]([Cl:41])[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(Cl)c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of methyl 2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-4-hydroxy-9H-pyrimido[4,5-b]indole-7-carboxylate (0.395 g, 0.757 mmol) in phosphorus oxychloride (6 mL, 64.4 mmol) was heated to 90° C. for 2 hours then after cooling, it was concentrated to dryness to give 650 mg as a brown foam which was suspended in sat. NaHCO3 (15 mL) and stirred for 1 hour. The solid was filtered, washed with water (3×2 mL) and dried at 40° C. under high vacuum until constant weight to afford methyl 2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (375 mg, 92% yield) as a tan solid and used as such in the next step: MS m/z 540.2 (M+H)+; HPLC 92%, RT 2.51 minutes.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:20]=[C:6]2[CH:7]=[N:8][C:9]3[C:14](=O)[C:13]([CH3:16])=[CH:12][N:11]([CH2:17][CH2:18][CH3:19])[C:10]=3[N:5]2[CH2:4]1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:9]2[N:8]=[CH:7][C:6]3[N:5]([CH2:4][N:3]([O:2][CH3:1])[CH:20]=3)[C:10]=2[N:11]([CH2:17][CH2:18][CH3:19])[CH2:12][C:13]=1[CH3:16]
Reactant: CCCn1cc(C)c(=O)c2c1N1CN(OC)C=C1C=N2
Reactant: O=P(Cl)(Cl)Cl
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16 g of 8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-4-one and 120 ml POCl3 are mixed and heated up to reflux for 8 hours. After cooling to room temperature the reaction mixture is treated with 1200 ml crushed ice/water and stirred for 1 hour. The product is extracted with 2×300 ml dichloromethane. The collected organic layer is washed with 2×300 ml water and dried with Na2SO4. The solvent is removed under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)cs1
Temperature: 25 °C

Procedure:
25 g (131 mmol) of 4-bromo-thiophene-2-carbaldehyde were dissolved in 180 ml of pyridine, and 16.34 g (157 mmol) of malonic acid and 1.11 g (13.1 mmol) of piperidine were added. The reaction mix was boiled under reflux for 6 h. After cooling to room temperature, the mixture was poured onto a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 21.15 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>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.O>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[C:25]([CH3:24])=[N:26][CH:27]=[CH:28][CH:29]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Temperature: 105 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
To 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.388 g, 0.992 mmol), 2-methylpyridin-3-ylboronic acid (0.176 g, 1.29 mmol), potassium acetate (0.389 g, 3.96 mmol), and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.049 mmol) was added DMF (20 mL) and water (1 mL). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 128 (115 mg, 28%). 1H NMR (400 MHz, DMSO) δ 8.44 (dd, J=24.8, 2.7, 2H), 8.10 (s, 1H), 7.69 (t, J=8.1, 1H), 7.35 (ddd, J=12.5, 7.9, 3.6, 2H), 7.19 (d, J=8.3, 1H), 5.74 (dt, J=13.2, 6.7, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.53 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 1-Methyl-1H-pyrazol-3-ylamine instead of 2-chloro-4-aminopyridine to yield [6-Methyl-2-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white solid. MS (ISP): m/e=332.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide as an off-white solid, MS (ISP): m/e=232.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light brown solid, MS (ISP): m/e=309.1 (M+H+).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].Br[CH2:17][CH2:18][O:19]C1CCCCO1.[OH-].[K+].O>CS(C)=O>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:17][CH2:18][OH:19]
Reactant: OCCc1ccccc1-c1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCCOCCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the alcohol prepared above (8.5 g, 43 mmol), 2-bromoethyltetrahydro-2-pyranylether (17.9 g, 86 mmol) and potassium hydroxide (9.6 g, 171 mmol) in dimethylsulfoxide (100 ml) was stirred at ambient temperature for 72 h. An extra batch of 2-bromoethyltetrahydro-2-pyranylether (3.6 g, 17 mmol) was added and the mixture stirred for 48 h at ambient temperature. Water (350 ml) was added and the mixture was extracted with diethylether (2×250 ml). The organic phases were combined, washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was submitted to column chromatography on silica gel (400 ml) using heptane and ethyl acetate (3:2) as eluent to give 6.6 g of 2-(2-(biphenyl-2-yl)ethoxy)ethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([C:21](O)=[O:22])[C:17]([F:20])=[C:18]([F:19])[C:12]=2[N:11]=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(OCC)(=O)C.C(#N)C>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:21]([C:16]2[C:17]([F:20])=[C:18]([F:19])[C:12]3[N:11]=[C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:14][C:13]=3[CH:15]=2)=[O:22])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Br)cc1)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F

Procedure:
2-(2,6-Dichlorophenylamino)-4,5-difluoro-1H-benzimidazole-6-carboxylic acid (150 mg 0.42 mmol), TEA (0.15 mL, 1.05 mmol), 4-bromoaniline (70 mg, 0.42 mmol) and 50% solution of PPA (0.3 mL 0.5 mmol) in ethyl acetate in 10 mL acetonitrile was stirred for a weekend at ambient temperature. Then the solvent was removed i.vac. The residue was purified by HPLC.