Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[N+:13]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: NOCC(O)CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(NOCC(O)CN1CCCCC1)Nc1cccc([N+](=O)[O-])c1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 25 ml abs. chloroform and 1,64 g (0,01 mol) 3-nitrophenyl isocyanate in 20 ml abs. chloroform was added thereto while stirring. After 1 hour reaction the mixture was evaporated and purified by column chromatography. The oil thus obtained was crystallized from diethyl ether. Yield: 1,84 g (54%). Mp.: 137-139° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[ClH:3].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:25][C:17]1[CH:18]=[CH:19][C:20]2[NH:21][C:22]3[N:23]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=4)[CH2:14][CH2:15][C:16]=1[CH:24]=2)[N:6]=[CH:5][C:4]=3[Cl:3])=[O:32]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1cccc(Cl)c1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 3-chlorobenzoyl chloride as the starting materials in 60% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.3.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[Li]CCCC.[C-]#[C-].[Li+].[Li+].[Br:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Br:18]/[C:19](/[CH:20]([OH:21])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CC(Br)=Cc1ccccc1
Reactant: C#CCCCCC#C
Agent: [C-]#[C-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCCC#CC(O)/C(Br)=C/c1ccccc1
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 1,7-octadiyne (254.4 mg, 2.4 mmol) in dry THF (50 mL) cooled at −78° C. was added nBuLi (1.6 M in hexanes, 1.5 mL, 2.0 mmol) followed by stirring at the same temperature for 10 minutes. To the previously prepared lithium acetylide solution was added a solution of α-bromocinnamaldehyde Compound 1 (422.0 mg, 2.0 mmol) in dry THF (5 mL) and the resultant mixture was stirred at −78° C. for 15 minutes. The reaction was then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 14 percent EtOAc in hexane) to give 613.1 mg (97 percent) of Compound 7: pale yellow oil; Rf=0.33 (14 percent EtOAc in hexane); IR (neat) 3397 (br), 3294, 2944, 2864, 2232, 2116, 1492, 1430, 1064 cm−1; 1H NMR (300 MHz, CDCl3) δ7.65-7.61 (m, 2H), 7.40-7.29 (m, 3H), 7.24 (s, 1H), 5.07 (br s, 1H), 2.68 (d, J=6.18 Hz, 1H, exchangeable with D2O), 2.34-2.27 (m, 2H), 2.26-2.19 (m, 2H), 1.96 (t, J=2.67 Hz, 1H), 1.74-1.62 (m, 4H); 13C NMR (75 MHz, CDCl3) δ135.4, 129.8, 129.1, 128.9, 126.8, 88.3, 84.8, 79.0, 69.4, 69.3, 61.2, 28.1, 27.9, 19.0, 18.6; MS (+CI) m/z (relative intensity) 318 (M+, 81Br, 4), 316 (M+, 79Br, 4), 220 (100).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc(Cl)c1O
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chloro-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 3.50-3.58 (m, 4H), 3.79 (s, 2H), 5.29 (s, 1H), 6.76-6.80 (m, 1H), 7.04-7.06 (m, 1H), 7.27-7.29 (m, 1H), 7.90 (s, 1H), 11.66 (br s, 1H). Mass spectrum (ES) MH+=321.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=O)[CH2:26]Br.O>CN(C=O)C>[C:12]([CH:9]1[CH2:8][CH2:7][C:6]2[NH:5][C:4](=[O:17])[N:3]3[CH:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[N:1]=[C:2]3[C:11]=2[CH2:10]1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCc2[nH]c(=O)nc(N)c2C1
Reactant: O=C(CBr)c1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1

Procedure:
A solution of 4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg) and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxed under nitrogen for 1.5 h. The solution was cooled and 40 mL water is added. The precipitate was collected and washed successively with 10 mL of methanol and 20 mL hot ethyl acetate to yield 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 1), m.p. 257°-277° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N+:29]([O-])=O)[C:12]([CH2:26][CH2:27][Cl:28])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.C(OC1C=C([N+]([O-])=O)C(Cl)=CC=1N)C1C=CC=CC=1.CCN=C=NCCCN(C)C.[CH3:62][O:63][C:64]1[CH:65]=[C:66]2[C:70](=[C:71]([O:75][CH3:76])[C:72]=1[O:73][CH3:74])[NH:69][C:68]([C:77](O)=[O:78])=[CH:67]2>[Pd].C1COCC1>[Cl:28][CH2:27][CH2:26][C:12]1[C:11]([NH:29][C:77]([C:68]2[NH:69][C:70]3[C:66]([CH:67]=2)=[CH:65][C:64]([O:63][CH3:62])=[C:72]([O:73][CH3:74])[C:71]=3[O:75][CH3:76])=[O:78])=[CH:10][C:9]([OH:8])=[C:17]2[C:13]=1[C:14]([C:22]([O:24][CH3:25])=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[NH:16]2
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Reactant: COC(=O)c1[nH]c2c(OCc3ccccc3)cc([N+](=O)[O-])c(CCCl)c2c1C(=O)OC
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2c(O)cc(NC(=O)c3cc4cc(OC)c(OC)c(OC)c4[nH]3)c(CCCl)c2c1C(=O)OC
Temperature: 25 °C
Yield: 19.9 %

Procedure:
10% Pd/C (0.035 g) was added to dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate (0.0718 g, 0.161 mmol) and chilled THF (5 mL) was added quickly to a flask. The mixture was placed under reduced pressure and purged three times with H2. The reaction was stirred under H2 at room temperature and atmospheric pressure until no starting material remained as indicated by TLC analysis. The solution was filtered through a Celite pad in a cinter funnel and washed with THF. The amine solution was concentrated under reduced pressure and the residue was co-evaporated twice with dry CH2Cl2 (3 mL each). To the amine were added EDCI (0.0617 g, 0.322 mmol) and 5,6,7-trimethoxyindole-2-carboxylic acid (0.0404 g, 0.161 mmol). The flask was sealed with a septum and flushed with N2. The mixture was then dissolved in dry DMF (6 mL) and stirred for three days under N2. The yellow solution was then diluted with ethyl acetate (150 mL), washed with water three times (100 mL each) and 5% NaHCO3 (50 mL). The organic layer was collected, dried with sodium sulfate, gravity filtered and concentrated under reduced pressure. The compound was purified on a chloroform silica gel column in which the solvent system was increased 0.5% MeOH/chloroform every 25 mL of solvent to give dimethyl 4-(2-chloroethyl)-7-hydroxy-5-(5,6,7-trimethoxyindole-2-carboxamido)indole-2,3-dicarboxylate as an off-white solid (17.8 mg, 0.032 mmol, 20% yield). Mp=166° C. (dec); TLC (2.5% MeOH/CHCl3) Rf320.23; 500 MHz 1H-NMR (CDCl3) 9.24 (s, 1H), 9.19 (s, 1H), 8.50 (s br, 1H), 7.25 (s, 1H), 7.10 (s br, 1H), 6.98 (s, 1H), 6.85 (s, 1H), 4.09 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 3.90 (t, 7.0, 2H), 3.31 (t, 7.0, 2H); IR (neat) 3282, 3090, 2954, 2918, 2851, 1730, 1713, 1685, 1610, 1535, 1510, 1476, 1415, 1376, 1307, 1262, 1204, 1096, 1050, 1030, 802. FAB-MS m/z (relative intensity) 560 (M+H+, 3), 559 (M+, 2). Accurate mass for C26H26N3O935Cl: calcd. 559.1358, obsd. 559.1350.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][OH:33])[CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][OH:33])[CH2:27]1)=[O:13])[CH2:8]2
Reactant: OCC1CCCNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCCC(CO)C1

Procedure:
5-(3-Hydroxymethyl-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-piperidinemethanol. Mass spectrum (ES) MH+=435.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[N:34]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35]1.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[N:34]1([CH2:37][CH2:38][O:39][C:21]2[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:19]([Cl:33])[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([C:10]4[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=4)[OH:9])[CH:17]=3)[N:22]=2)[CH2:36][CH2:35]1
Reactant: OCCN1CC1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN3CC3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), 2-(aziridin-1-yl)ethanol (16.2 μL, 0.20 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 20.2 mg, 0.51 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight, cooled and stirred at room temperature an additional night before workup. Reaction contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) to afford the title compound. MS (ESI): mass calcd. for C30H26Cl2N4O2, 544.1; m/z found, 545.1 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.31 (m, 1H), 7.28-7.23 (m, 6H), 6.18 (d, J=1.1 Hz, 1H), 4.51-4.44 (m, 2H), 3.37 (s, 3H), 2.50-2.39 (m, 2H), 1.48-1.37 (m, 2H), 0.97-0.94 (m, 2H).
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:14]=[C:13]([S:15][CH3:16])[NH:12][C:11](=O)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:20][C:11]1[CH:10]=[C:9]([CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:14]=[C:13]([S:15][CH3:16])[N:12]=1
Reactant: CSc1nc(COC2CCCCC2)cc(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc(Cl)cc(COC2CCCCC2)n1

Procedure:
To a mixture of 6-cyclohexyloxymethyl-2-methylsulfanyl-3H-pyrimidin-4-one (20 mg) in dichloromethane (2 mL) and dimethylformamide (catalytic amount) was added thionyl chloride (47 mg). The mixture was heated at reflux for 1.5 h. The solvent was removed under vacuum to give 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanylpyrimidine, which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[C:14]=3[CH:28]=2)=[O:9])=[CH:6][CH:5]=1.I[CH3:32]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH3:32])[C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[C:14]=3[CH:28]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CI
Reactant: O=C1CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
NaH 80% in oil (0.0366 mol) was added at 10° C. under N2 flow to a mixture of intermediate (6) (0.0244 mol) in N,N-dimethylformamide (100 ml). The mixture was brought to room temperature and then stirred for 30 min. and iodomethane (0.0293 mol) was added. The mixture was stirred for 3 hours, hydrolyzed, filtered, washed with water and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (9.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 4.5 g (43%) of 7-(4-chlorobenzoyl)-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (intermediate 7), mp. 176° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].CN.[CH2:37]([N:39](CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:39][CH3:37])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), methylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23 mg, 73% of theory).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: OCCc1ccc2c(n1)NCCC2
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Br)Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.17 g, 0.96 mmol) and polymer bound PPh3 (0.32 g, 0.96 mmol) in dry THF (10 mL) was added ethyl [2,2-dibromo-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, polymer was filtered through Celite and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (0.14 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 50 mg (12%) of desired product. 1H NMR (CD3OD) δ 7.59 (d, 1H, J=7.4 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.7 Hz), 6.73 (d, 1H, J=7.2 Hz), 4.27 (t, 2H, J=6.0 Hz), 3.49 (t, 2H, J=5.9 Hz), 3.14 (t, 2H, J=5.9 Hz), 2.82-2.78 (m, 3H), 2.71-2.59 (m, 2H), 2.25-2.19 (m, 1H), 1.97-1.90 (m, 2H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)ccc2c(Cl)ccnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(SCc2ccccc2)ccc2c(Cl)ccnc12
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a vial charged with 7-bromo-4-chloro-8-methylquinoline (0.950 g, 3.70 mmol) was added Dioxane (14.81 ml), DIEA (1.294 ml, 7.41 mmol), xantphos (0.429 g, 0.741 mmol), Pd2(dba)3 (0.339 g, 0.370 mmol) and benzyl mercaptan (0.438 ml, 3.70 mmol). The vessel was sealed and heated to 110° C. for 3 hr affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product as a yellow oil as a mixture of mono and bis substituted product according to MS as one LC peak, 7-(benzylthio)-4-chloro-8-methylquinoline (1.100 g, 3.67 mmol, 99% yield). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].Cl[CH2:13][C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(OCC)(=O)C>CN(C)C=O>[CH:17]([O:16][C:14]([CH2:13][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:15])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccncc1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
4 g (42.06 mmol) of 4-hydroxypyridine was dissolved in 80 ml of N,N-dimethylformamide, and 8.7 g (62.92 mmol) of pottasium carbonate and 16.45 g (63 mmol) of benzhydryl α-chloroacetate were added thereto. After stirring for 4 hours at 60° C., 200 ml of ethyl acetate was added to the reaction solution, and washed with water and a saturated sodium chloride aqueous solution followed by drying over anhydrous sodium sulfate and treating with active carbon. The solvent was distilled off under reduced pressure, and the crystal residue was washed with ether to obtain 9.8 g (yield: 73%) of 1-benzhydryloxycarbonylmethyl-4-pyridone.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[CH3:17][O-:18].[Na+].Cl>CO>[OH:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:8]([C:2]([O:18][CH3:17])=[O:1])[CH2:9]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
tert-butyl(1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate (5.65 g, 25.0 mmol) was suspended in methanol (20 mL). To that suspension was added a 25 wt % solution of sodium methoxide in methanol (52 mL) and the reaction mixture was stirred at rt for 2 h. Then it was cooled into an ice-water bath and neutralized with a 4 M HCl solution to pH 6. After removing the volatiles, brine was added (50 mL) and the solution was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the desired product (5.70 g, 88.4% yield). LCMS: m/z 281.1 (M+Na)+.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[S:58]1[CH:62]=[CH:61][CH:60]=[C:59]1[S:63](Cl)(=[O:65])=[O:64]>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:59]3[S:58][CH:62]=[CH:61][CH:60]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and thiophene-2-sulfonyl chloride (80 mg, 0.437 mmol), the title compound was obtained as a white solid (93 mg, 65% yield). MS (ESI): 489.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][O:15]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:14]=[O:15])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1CCC(=O)N2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1CCC(=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
5-Methoxy-3,4-dihydro-1H-quinolin-2-one (5.00 g, 26 mmol) was dissolved in dichloromethane (100 ml), and dichloromethyl methyl ether (7.65 ml, 85 mmol) was added at 0° C. Titanium tetrachloride (12.4 ml, 113 mmol) was added dropwise at a temperature not higher than 10° C. Stirring was carried out at room temperature for 2 hours, and the reaction mixture was poured into ice water and separated into layers. The aqueous layer was subjected to extraction with dichloromethane. The organic layers were combined and washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, diethyl ether was added, and the produced insoluble matter was collected by filtration and dried to thereby obtain 5.32 g (yield: 92%) of 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxaldehyde as a light brown powder.