Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Product: COc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-methoxyaniline in a similar manner as described in Example 13 to give 32 mg (21% yield) of a brown solid. 1H-NMR (CDCl3): δ 8.13 (s, 1H), 7.50 (d, 1H), 7.23 (dd, 1H), 7.14 (dd, 1H), 6.92-6.84 (m, 2H), 6.79-6.73 (m, 2H), 4.76 (m, 1H), 3.83 (s, 3H), 2.74 (m, 2H), 2.28 (m, 1H), 2.08 (m, 1H), 1.98-1.75 (m, 2H); MS m/z 325 (M−1).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](NC3C=CC(N4CCN(C)CC4)=CC=3)=N2)=[CH:4][CH:3]=1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH:37]=3)=[N:33]2)=[CH:28][CH:27]=1>>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:38]2[CH:37]=[C:36]([NH:35][C:32]3[N:31]=[CH:30][C:29]4=[CH:28][CH:27]=[C:26]([NH:10][CH2:2][C:3]5[CH:8]=[N:7][CH:6]=[CH:5][CH:4]=5)[N:34]4[N:33]=3)[CH:41]=[CH:40][CH:39]=2)[CH2:43][CH2:44]1
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(Br)n4n3)c2)CC1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(NCc5cccnc5)n4n3)c2)CC1

Procedure:
The titled compound was prepared in an analogous fashion to Example 1164 replacing (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine with (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine to give a yellow solid (65 mg, 60%). LCMS (E/I+) 415.19 (M+H). NMR 1H (DMSO-d6)-9.90 (bs, 1H), 1.41 (s, 1H), 8.73 (s, 1H), 8.62 (d, 1H, J=4.97 Hz), 8.4 (s, 1H), 8.06 (d, 1H, J=7.45 Hz), 7.61 (t, 1H, J=5.79 Hz), 7.48 (bs, 1H), 7.37 (d, 1H, J=7.45 Hz), 7.24 (d, 1H, J=7.45 Hz), 7.19 (s, 1H), 7.16 (d, 1H, J=4.97 Hz), 6.70 (d, 1H, J=8.28 Hz), 6.66 (d, 1H, J=4.57 Hz), 4.71 (s, 2H), 3.86 (bs, 2H), 3.47 (bs, 2H), 3.14 (bs, 2H), 2.98 (bs, 4H), 2.86 (s, 3H).
Reaction SMILES: Cl.[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4].Cl.[C:21]([N:29]1[CH2:34][CH2:33][CH2:32][C:31]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=2)([CH2:35][CH2:36][CH2:37]N2CCC(C(N3CCCC3)=O)CC2)[CH2:30]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[ClH:57].[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH2:37][CH2:36][CH2:35][C:31]2([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=3)[CH2:32][CH2:33][CH2:34][N:29]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:30]2)[CH2:12][CH2:13]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4]
Reactant: C=CC(=O)N(C)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1 and 0.3 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.2 g of the expected product, m.p.=128° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:12].C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[Cl:12][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:19]1([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]1)=[CH:11]2
Reactant: Clc1ccnc2cc(Br)cnc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(Cl)ccnc3c2)CC1
Temperature: -78 °C
Yield: 38 %

Procedure:
Dissolved 3-bromo-8-chloro-1,5-naphthyridine (210 mg, 862 μmol) in 8 mL of THF and cooled to −78° C. Then added butyllithium (517 μl, 1294 mol) and stirred for 15 min. Added tert-butyl 4-oxopiperidine-1-carboxylate (258 mg, 1294 μmol) and let warm to room temperature over 1 h. The reaction was quenched with saturated NH4Cl and extracted with dichloromethane (3×20 mL), dried over NaSO4 and concentrated. Intermediate was purified via MPLC (DCM/MeOH/NHOH) to yield tert-butyl 4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (120 mg, 38% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18]O)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([Cl:14])[C:5]=2[N:15]=1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:14][C:6]1[C:5]2[N:15]=[C:2]([NH2:1])[N:3]([CH2:16][CH2:17][CH2:18][Cl:22])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Nc1nc2c(Cl)nc3ccccc3c2n1CCCCl
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 103.6 %

Procedure:
To a round-bottomed flask containing 3-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (7.17 g, 25.9 mmol) was added 1,2-dichloroethane (210 mL) and the suspension was stirred for 5 minutes. To the stirred suspension was added thionyl chloride (5.6 mL, 77.7 mmol) and the reaction was heated to 50° C. overnight. The reaction was cooled to ambient temperature, filtered, and the residue was washed with 1,2-dichloroethane (100 mL) and diethyl ether (3×100 mL) to afford the product. The product was dried under reduced pressure to afford 4-chloro-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-2-amine (7.92 g) as a light brown solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[NH:8][C:7]=1[NH2:19])=[O:5])C.[CH3:20][N:21](C=O)C.C(N)=O>C(O)=O>[OH:5][C:4]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)[NH:8][C:7]=2[N:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)[nH]c1N
Reactant: CN(C)C=O
Solvent: O=CO
Solvent: NC=O
Product: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Temperature: 150 °C

Procedure:
A mixture of 36.6 g (0.143 mol) 2-amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, 140 ml DMF, 305 ml formamide and 14.6 ml 85% formic acid is heated for 16 h at 150° C. The resulting yellow suspension is cooled to 10° C. and filtered. The solid is washed with methanol (120 ml) and ether (150 ml) and dried. The title compound is obtained as yellowish crystals; m.p. >410° C.; MS-ES+: (M+H)+=254.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of 3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) and potassium carbonate (3.8 g, 27 mmol) in THF (25 mL) and water (25 mL) was added benzyl carbonochloridate (4.6 g, 27 mmol) at 0° C. and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum) to give 3-benzyloxycarbonylamino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 5.14-5.02 (m, 2H), 4.88-4.79 (m, 1H), 3.63-3.23 (m, 4H), 2.25 (m, 1H), 1.88-1.77 (m, 1H), 1.45 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](C3C=CC(OC(C)C)=CC=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.C(OC1C=CC(B(O)O)=CC=1)(C)C.[F:62][C:63]1[CH:64]=[C:65](B(O)O)[CH:66]=[CH:67][C:68]=1[O:69][CH2:70][CH2:71][CH3:72]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:65]3[CH:66]=[CH:67][C:68]([O:69][CH2:70][CH2:71][CH3:72])=[C:63]([F:62])[CH:64]=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Reactant: CCCOc1ccc(B(O)O)cc1F
Agent: CC(C)Oc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1F

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS#192376-68-4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:29]([OH:34])[OH:30])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2cccc3ccccc23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Temperature: -60 °C
Yield: 68.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 208.8 g (737.4 mmol) of 1(4-bromophenyl)naphthalene and 2.1 L of dehydrated THF was cooled down to −60 degrees C., and added with 567 ml (884.9 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degree C. 416 g (2.21 mol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 4-(1-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]1=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)Cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(=Cc2ccc(Cl)cc2)C(Br)c2ccccc21
Temperature: 25 °C

Procedure:
2-(4-chlorobenzylidene)indan-1-one (2.44 g, 9.58 mmol) was dissolved in 35 mL of CCl4. N-bromosuccinimide (1.685 g, 9.58 mmol) and benzoyl peroxide (122 mg, 0.52 mmol) were added in one portion. The solution was then stirred under reflux for one hour and then filtered once cooled to room temperature. The precipitate was separated using flash column chromatography (15:1 Hexanes/EtOAc) provided 14a as white crystals.
Reaction SMILES: BrC1C(Br)=C([C:12]([O:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19](Br)[C:18]=2Br)=[O:16])=[O:13])C2C(C=1)=CC=CC=2>CCOCC>[CH:23]1[CH:22]=[C:21]2[C:26]3=[C:25]([C:12]([O:14][C:15](=[O:16])[C:17]3=[CH:18][CH:19]=[CH:20]2)=[O:13])[CH:24]=1
Reactant: O=C(OC(=O)c1c(Br)c(Br)cc2ccccc12)c1c(Br)c(Br)cc2ccccc12
Solvent: CCOCC
Product: O=C1OC(=O)c2cccc3cccc1c23
Temperature: 25 °C

Procedure:
The following morning thin-layer chromatography showed only a trace presence of the dibromonaphthalic anhydride. The reaction mixture was cooled to room temperature followed by the addition of 350 ml of ether. The. triethylamine hydrobromide byproduct was removed by filtration. The filtrate was concentrated on the rotary evaporator, to give the diphenylethynyl derivative of the 1,8-naphthalic anhydride.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12].[OH-].[K+].C(OCC)(=O)C.CCCCCC>O.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12]
Reactant: CSc1ccc(C(=O)C(=O)O)cc1Cl
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To hydrazine hydrate (10 g, 5 eq) cooled at −50° C., 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetic acid (10 g, 0.04 mol) was added. The contents were initially warmed to room temperature and slowly heated to 80° C. Then KOH (5.59 g, 2.3 eq) was added portion wise at 80° C. and the overall reaction mass was allowed to reflux for 12-16 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, the reaction contents were diluted with a mixture of water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). Then the aqueous layer was acidified with diluted HCl and allowed to stir for 1 h at room temperature. The precipitate was filtered and dried to yield 2-(3-chloro-4-(methylthio)phenyl)acetic acid as a white colored solid (8 g, 85%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][C:42]3[N:41]4[C:36]([CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:35][C:34]=3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:28][N:27]([CH3:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][C:42]3[N:41]4[C:36]([CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:35][C:34]=3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:28][N:27]([CH3:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CC(c2ccc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A mixture of 244d (90 mg, 0.15 mmol) and lithium hydroxide (60 mg, 1.5 mmol) in THF/i-propanol (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (3 mL). It was then extracted with ethyl acetate (20 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 244 (25 mg, 30%) as white solid. MS-ESI: [M+H]+ 566.4. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=2.5 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.59-7.57 (m, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.85-6.83 (m, 1H), 6.33 (s, 1H), 5.04-5.01 (m, 1H), 4.67-4.65 (m, 1H), 4.44-4.39 (m, 1H), 4.33-4.29 (m, 1H), 3.95-3.91 (m, 1H), 3.86-3.83 (m, 2H), 3.76-3.74 (m, 1H), 3.73 (s, 3H), 3.62-3.59 (m, 1H), 3.16-3.13 (m, 2H), 3.02-2.95 (m, 2H), 2.84-2.83 (m, 2H), 2.39 (s, 3H), 2.05-2.02 (m, 2H), 1.90-1.87 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][OH:41]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:39][CH2:40][OH:41])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCN(CCO)CC3)c2)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 68.7 %

Procedure:
To a mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 210 mg; 0.46 mmol), K2CO3 (189 mg; 1.37 mmol) and KI (3 mg; 0.018 mmol) in DMF (5 mL) was added 2-bromoethanol (115 mg; 0.92 mmol) under nitrogen. The reaction mixture was stirred at 100° C. for 15 hours, concentrated, and purified by preparative TLC (DCM/MeOH=10/1) to afford 148 mg (69%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2.[CH2:26]([S:28]([CH2:31][CH2:32][CH2:33]O)(=[O:30])=[O:29])[CH3:27]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:33][CH2:32][CH2:31][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2
Reactant: CCS(=O)(=O)CCCO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Product: CCS(=O)(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)c(C)c4c3)c2cc1OC
Yield: 0.1 %

Procedure:
Using an analogous procedure to that described for Example 124, 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (120 mg, 0.36 mol), (prepared as described for the starting material in Example 91), was reacted with 3-(ethylsulphonyl)-1-propanol (71 mg, 0.46 mol), (prepared as described for the starting material in Example 124), to give 4-(2,3-dimethylindol-5-yloxy)-7-(3-ethylsulphonylpropoxy)-6-methoxyquinazoline (96 mg, 57%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:40][CH:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a mixture of 0.11 g (0.27 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20), 0.19 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.30 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.13 g (0.30 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.10 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-21) as a white solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][CH2:9][CH2:10]CCC.CCOCC>C[O-].[Na+].C(O)CCC.CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC
Yield: 95.1 %

Procedure:
A 74.1g (0.1 mole) amount of n-butyl alcohol, 200.2g (2.0 mols) of methyl methacrylate, 187g (2.18 mols) of n-hexane and 0.17 g of hydroquinonemonomethyl ether were added to the apparatus described in Example 1 and were heated and agitated under full reflux to remove water from the reaction system. The amount of water obtained in the reaction solution was 0.001 mol. To the reaction solution was added 0.0035 mol of sodium methylate as a catalyst and the solution was heated and agitated. An azeotropic mixture was n-hexane and methanol fom the upper part (top) of the fractionating tower was obtained and was kept stationary in a decanter. The n-hexane layer which separated was returned to the tower and the methanol layer was removed continuously to advance the reaction. Meanwhile, the temperature at the top of the tower was 56° to 59.8° C and the flask temperature was 83° to 90° C. The results of the experiment were a 98.8% conversion of n-butyl alcohol and a 95.1% yield of n-butyl methacrylate. However, it was found bu gas chromatography that an additive of methylmethacrylate was produced as a by-product as well as a polymer. As soon as this reaction solution was distilled, it polymerized.