Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>CS(C)=O.O>[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH:42][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1cccc(N)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(N)c4)n3Cc3ccccc32)cc1C
Yield: 57.2 %

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (0.125 g; 0.275 mmol), and 3-aminobenzylamine (0.071 g; 0.577 mmol), in dimethylsulfoxide (5 mL) was stirred at 80° C. for 18 hours. The solution was diluted with water and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated to yield the title compound as an amorphous white solid (0.085 g; 57%), m.p. 105-115° C. MS [(+)ESI, m/z]: 541.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.C(N(CC)CC)C>CC(N(C)C)=O>[CH:29]1([CH2:32][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]4[O:13][C:9]([NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:10][N:11]=4)=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:31][CH2:30]1
Reactant: BrCC1CC1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(N2CCN(CC3CC3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41) (120 mg, 0.31 mmol) in DMA (2 mL) was placed in a microwave tube with cyclopropylmethyl bromide (88 mg, 0.62 mmol), and triethylamine (64 mg, 0.62 mmol). The mixture was heated with stirring in the microwave at 110° C. for 60 minutes then transferred directly onto a reverse phase HPLC column and eluted with a gradient of acetonitrile/water containing 0.2%/TFA to give the title compound (125 mg, 91%) as a solid; 1H NMR δ 10.65 (1H, s), 10.40 (1H, bs), 8.20 (1H, s), 7.65 (2H, m), 6.90 (2H, m), 6.80 (1H, m), 6.65 (1H, d), 4.00 (2H, d), 3.25 (2H, d), 2.80 (6H, m), 0.75 (1H, m), 0.30 (2H, m), 0.00 (2H, m); MS m/e MH+ 438.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[Se:26][C:25]=1[C:33]([NH2:35])=[O:34].CN(C=O)C.[OH-].[Na+]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:28]=[C:27]([C:29]([CH3:32])([CH3:30])[CH3:31])[Se:26][C:25]=3[C:33]([NH2:35])=[O:34])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nc(-c3ccc(Cl)cc3)nc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(Cl)cc3)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
The reaction of 4-chloro-2-(4-chlorophenyl)-6,7-dimethoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a white color solid, mp 268-270° C. 1H NMR (400 MHz, CDCl3): δ 12.03 (1H, s, exchangeable with D2O), 9.05 (1H, s), 8.49 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.37 (1H, s), 7.32 (1H, s), 5.37 (2H, s, exchangeable with D2O), 4.11 (3H, s), 4.06 (3H, s), 1.52 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.6, 168.5, 158.1, 155.0, 154.8, 149.9, 148.5, 148.1, 137.7, 136.0, 129.4, 128.5, 122.0, 109.3, 108.4, 108.0, 100.3, 56.3, 56.2, 37.3, 32.7; LC-MS (negative ion mode): m/z 541, 543, 545 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:5].[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:50]=[CH:49][C:35]3[N:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=5)[N:39]=[C:37]4[S:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C1C=CN=CC=1.C1COCC1>[OH:7][CH2:6][C:3]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14]([NH:48][C:45]2[CH:44]=[CH:43][C:42]([C:40]3[N:39]=[C:37]4[N:36]([CH:41]=3)[C:35]3[CH:49]=[CH:50][C:32]([O:31][CH2:30][CH2:29][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:33][C:34]=3[S:38]4)=[CH:47][CH:46]=2)=[O:22])[CH:9]=1)([CH2:2][OH:1])[CH2:4][OH:5]
Reactant: O=C(Nc1cc(C(CO)(CO)CO)on1)Oc1ccccc1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1)Nc1cc(C(CO)(CO)CO)on1

Procedure:
A mixture of phenyl 5-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)isoxazol-3-ylcarbamate (1 equivalent), 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (4) (1 equivalent) and 4-(dimethylamino)pyridine (0.05-0.5 equivalents) in anhydrous THF is stirred at a temperature between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The reaction mixture is concentrated under reduced pressure and the residue is purified by either preparative reverse-phase HPLC or silica gel flash chromatography to afford 1-[5-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1b).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4].O=[C:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[OH:4])[CH3:33])=[CH:27][CH:26]=1)=[O:30]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Oc2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Oc3ccccc3)c2)cc1
Yield: 33.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-phenoxyphenyl)ethanol (prepared as described in Preparation 15), 3.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 3.7 g of sodium cyanoborohydride, 1.27 g of the title compound were obtained having an Rf=0.26 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][N:3]1[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCCNC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccccc2C1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (10 g, 54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0° C. Triethylamine (18.21 mL, 130.6 mmol) was added followed by the dropwise addition of acetic anhydride (6.18 mL, 65.3 mmol) in dry dichloromethane (50 mL). The reaction was then stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The resulting mixture was washed with 1 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give 10 g of product as colorless oil (yield was 97%). It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 190.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:33]([O:22][CH2:21][CH2:20][CH2:19][C@H:18]([C@@H:17]1[C@:24]2([CH3:32])[C@H:14]([C@H:13]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:10]([CH2:9][C@@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:30][CH2:29]2)=[CH:11][CH2:12]3)[CH2:15][CH2:16]1)[CH3:23])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Compound 2002 (7.6 g, 17 mmol) in dry CH2Cl2 (300 ml) was treated with a solution of t-butyldimethylsilylchloride (TBDMSCl, 1.0M) and imidazole (0.5M) in dry CH2Cl2 (38.0 ml, 38.0 mmol TBDMSCl). The solution was stirred at room temperature under argon overnight. The resultant solution was poured into an aqueous saturated NaHCO3 solution and the mixture extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. The resultant solid was purified by flash chromatography (SiO2, hexanes:EtOAc gradient from 20:1 to 5:1) giving compound 2003 (9.4 g, 17 mmol, 98%). 1H NMR (500 MHz, CDCl3) δ: 5.38-5.32 (m, 1H, C-6 H), 4.72 (brs, 1H, THP methine H), 3.95-3.88 (m, 1H, THP CH2O), 3.60-3.46 (m, 4H THP CH2O & C-3 H & C-24 H), 1.01 (S, 3H, C-19 H), 0.93 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.67 (s, 3H, C-18 H), 0.05 (s, 6H, TBDMS CH3); IR (CHCl3) 2900 cm-1 ; MS (CI/isobutane) m/z 559 (M-1, 1%), 474 (M+1-THP, 12%), 457 (M+1-THPOH, 18%), 343 (M+1-THP-TBDMSOH, 6%), 325 (M+1-THPOH-TBDMSOH, 100%); m.p. 116°-118° C.; Anal. calcd. for C35H62O3Si: C=75.21, H=11.18; Found: C=75.37, H=11.24.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])C.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH3:19][N:10]1[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=2[C:8]2[CH2:7][CH:6]([C:4]([NH:23][CH2:21][CH3:22])=[O:5])[CH2:20][C:9]1=2
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Reactant: CCN
Solvent: CCO
Product: CCNC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Temperature: 90 °C
Reaction time: 120 h
Yield: 47.7 %

Procedure:
In a 50 ml sealed tube was dissolved 1,2,3,4-tetrahydro-4-methyl-7-methoxycyclopent[b]indole-2-carboxylic acid ethyl ester (2.8 g, 0.01 mole)in 25 ml of ethanol. To this was added an aqueous solution of ethylamine (70% solution, 5 ml, 0.075 mole). After stirring at 90° C. for five days, the mixture was concentrated to a brown solid, (~3 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined to yield 1.3 g of a white solid, m.p. 162°-3° C. A sample of this material (0.5 g) was recrystallized from ethyl acetate/ether (1:10) to give the product as white crystals, 0.4 g, m.p. 163°-4° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:54]=[N+:55]=[N-:56])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[N:54]([C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])=[N+:55]=[N-:56]
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Dissolve trans-2-methyl-cyclohexanol (5.0 g, 44.0 mmol) in anhydrous THF (500 mL) and cool to −20° C. Add triphenylphosphine (57.43 g, 218.9 mmol), diethyl azodicarboxylate (38.13 g, 218.9 mmol), and diphenylphosphoryl azide (60.25 g, 218.9 mmol) respectively under nitrogen. Stir the reaction mixture for 6 hours at the same temperature then warm it to room temperature and stir overnight Add water (500 mL), and extract the aqueous layer with EtOAc (3×500 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-25% of EtOAc/Hexane) to give 3.98 g (65%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 3.08-3.16 (m, 1H), 1.90-1.98 (m, 1H), 1.56-1.78 (m, 3H), 1.16-1.35 (m, 4H), 1.01 (d, 3H), 0.93-1.03 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: Cc1ccc(CN)c(C)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: Cc1ccc(CNC(=O)C(C)c2cccc3cnccc23)c(C)c1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,4-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 319 (M+H)+; MS (ESI−) m/z 317 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.52 (d, J 7.1, 3H), 2.13 (s, 3H), 2.21 (s, 3H), 4.20 (m, 2H), 4.51 (q, J 7.1, 1H), 6.88 (d, J 7.5, 1H), 6.94 (s, 1H), 6.98 (d, J 7.5, 1H), 7.82 (t, J 7.8, 1H), 7.99 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.35 (d, J 6.4, 1H), 8.44 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]([O-:29])(O)=O.[Na+]>CO.N1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11]([N:12]2[CH2:13][CH2:26][O:29][CH2:10][CH2:11]2)[C:10]=1[C:24]#[N:25]
Reactant: O=C([O-])O
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCN1
Product: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(N3CCOCC3)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
An amount of 50 mg (0.117 mmole) of 47a was dissolved in 500 μL, of MeOH, 1 ml of morpholine and 512 mg (6.203 mmole) of NaHCO3. The mixture was heated to 80° C. for 1 hr to give 5-(2-Bromo-5-fluoro-phenyl)-1,3-dimethyl-7-morpholin-4-yl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (47b).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:5][C:4]=1[F:17].C(=O)(O)[O-:19].[Na+]>CS(C)=O>[F:17][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: COc1cccc(-c2ccc(CBr)c(F)c2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc(C=O)c(F)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromomethyl-3-fluoro-3′-methoxy-biphenyl (0.45 g, 1.5 mmol) in dimethyl sulfoxide (10 mL) was added sodium bicarbonate (1.79 g, 21.3 mmol) and the resulting mixture was then stirred at 100° C. for 2 h. After the reaction was completed, it was cooled to room temperature and quenched with brine solution. The mixture was extracted with diethylether (50 mL×2) and the combined ether layers were washed with water, dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 4% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>O.[Fe]>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A flask equipped with an overhead stirrer and condenser was charged with 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (25 g, 0.081 mol) and 150 mL of ethanol, followed by 45 g (0.805 mol) of iron powder. An equal amount of saturated ammonium chloride solution was added and the mixture was brought to 80° C. After 5 hours of heating, the mixture was allowed to cool to ambient temperature, diluted with water (500 mL) and filtered through GF/F filter paper multiple times to remove the iron and iron salts. The filtrate was extracted with EtOAc, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (1:1 ethyl acetate/hexane to 100% ethyl acetate) afforded 12.6 g (56%) of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[CH:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:32]=[N:33][N:34]=[CH:35]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cnnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K68) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (79 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:27]=[O:28])C.P(Cl)(Cl)(Cl)=O>O>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:18]2[CH:23]=[CH:22][C:21]([CH:27]=[O:28])=[CH:20][CH:19]=2)[C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)c(C)c2)cc1C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 0 °C

Procedure:
124.6 g of [N,N-bis-(3,4-dimethylphenyl)amino]benzene and 35.5 mL of DMF were placed in a three-neck flask. While stirring and cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. Upon completion of addition of drops, the mixture solution was reacted for 5 hours at 95° C., poured into 4 L of warm water, and stirred for 1 hour. The precipitate was collected and washed in a :1:1 mixture solution of ethanol/water. 4-[N,N-bis-(3,4-dimethylphenyl)amino]benzaldehyde was obtained. The yield was 107.6 g (yield rate of 79.0%).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:8][NH:9][O:10][CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:11][O:10][N:9]([CH3:8])[C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydrochloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40° C.) to afford the product (1.33 g, 88%). 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:17]C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(Cl)s1)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a solution of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2,2-trifluoroacetamide (3.118 g) in methanol (MeOH) (50 mL) solution of potassium carbonate (K2CO3) (6.4 g) in water (25 mL) was added and the reaction mixture was stirred until reaction completion (24 hours) at room temperature. The obtained reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (NaHCO3) and evaporated to give 2.26 g of dark brown oil which was used in the next step without further purification. 1H NMR (DMSO-d6): 2.71 (s, 3H, NMe), 4.47 (s, 2H), 4.71 (br. s, 2H, NH2), 6.67-6.75 (m, 3H), 6.82 (d, 1H), 6.93 (d, 1H). LC/MS (m/z) 288.0 ([M+H]+); RT=2.07, (UV, ELSD) 85%, 98%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:51][CH2:50][N:42]2[C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:52])(=[O:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[CH:26][CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(C4CC4)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 114b (200 mg, 0.645 mmol), 114a (0.903 mmol), Pd(PPh3)4, Na2CO3 aqueous solution (1.0 N, 2.13 mL, 2.13 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. DCM (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 2-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 114c, it was directly used in the next step.