Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[S-2:24].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][S:24]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [S-2]
Reactant: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCS1
Temperature: 40 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
To a solution of crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) in methanol (25 ml) was added sodium sulfide monohydrate (0.84 g). The reaction mixture was stirred at 40° C. for 3 hours. The methanol was partially removed by distillation. Water was added and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified over silica gel (ethyl acetate/heptanes, from 1:4 to 1:1) to give thietan-2-ylmethyl-carbamic acid tert-butyl ester (0.15 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:9]=1)(C)(C)C.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]2[CH2:15][CH2:16][N:17]([C:29](=[O:30])[CH2:28][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH2:18][CH2:19]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2CCNCC2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)N2CCC(c3cccc(N)c3)CC2)CC1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
(3-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.22 g (73%) of 1-[4-(3-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. (3-(1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl-1-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.18 g) (81%) of 1-[4-(3-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[3-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone di-TFA salt (38.5 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (17 mg, 0.16 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 16.5 mg of 2-{3-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 9.08 (br s, 1H), 8.40 (s, 1H), 7.44 (s, 1H), 7.17-7.29 (m, 4H), 7.08 (dd, 1H, J=1.9 Hz, J=7.9 Hz), 6.85 (d, 1H, J=7.6 Hz), 4.29 (q, 2H, J=7.1 Hz), 3.02 (br s, 2H), 2.88-2.93 (m, 5H), 2.66-2.73 (m, 2H), 2.32 (s, 6H), 2.05-2.12 (m, 2H), 1.75-1.84 (m, 2H), 1.55 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: CC(N(C)C)=O.[SH:7][C:8]1[N:13]2[N:14]=[C:15]([C:17]([OH:19])=O)[N:16]=[C:12]2[N:11]=[C:10]([CH3:20])[CH:9]=1.ClC(N(C)C)=C(C)C.Cl.[CH3:30][NH:31][OH:32].C(N(C(C)C)C(C)C)C>CC(N(C)C)=O>[OH:32][N:31]([CH3:30])[C:17]([C:15]1[N:16]=[C:12]2[N:11]=[C:10]([CH3:20])[CH:9]=[C:8]([SH:7])[N:13]2[N:14]=1)=[O:19]
Reactant: Cc1cc(S)n2nc(C(=O)O)nc2n1
Reactant: CNO
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(S)n2nc(C(=O)N(C)O)nc2n1
Temperature: -10 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylic acid dimethylacetamide (0.99 g) (3.33 mmol) is suspended in 15 ml of absolute dimethylacetamide and treated while stirring with 530 mg (3.96 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine. After 4 hours the solution is cooled to -10° C. and treated while stirring with 550 mg (6.6 mmol) of N-methylhydroxylamine hydrochloride and 860 mg (6.6 mmol) of ethyl-diisopropylamine. The reaction mixture is stirred at room temperature for 18 hours and subsequently concentrated in a high vacuum. The residue is crystallized using water and recrystallized from dimethylformamide/diethyl ether. There is obtained 0.50 g of N-hydroxy-7-mercapto-N,5-dimethyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as yellow crystals of melting point 215° C. (dec.).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:37]([NH:39][C@H:40]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:41][OH:42])=[O:38])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:36])[NH:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:37]([NH:39][C@H:40]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:41][OH:42])=[O:38])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:36])[NH:25][S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:28])=[O:27])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
1.50 Grams of Boc-Leu-Gln-Arg(Tos)-Ser-Ser-OH was treated with 10 ml of trifluoroacetic acid at a room temperature to remove the tert-butoxycarbonyl group therefrom, dried ether was added to the reaction mixture to crystallize the desired product to obtain H-Leu-Gln-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])#[N:15]>C1COCC1>[CH:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][C:9]=1[CH:19]([OH:20])[C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[C:14]#[N:15])=[O:13]
Reactant: O=Cc1cccnc1
Reactant: N#Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccncc2C=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N,N′-trimethylethane (1.55 mL, 12 mmol) was dissolved in THF (30 mL) and cooled to −78° C. 2.5 M n-butyllithium (4.4 mL) was added into the reaction mixture, which was then stirred for 15 min, before the addition of pyridine-3-carbaldehyde (0.94 mL, 10 mmol). The reaction mixture was maintained at −78° C. for 15 min, then n-butyllithium (8 mL) was added slowly so that the temperature was always below −42° C. The reaction mixture was stirred 1 hour at 42° C., then cooled to −78° C. before it was transfer through a cannula into a solution of 3-cyanobenzaldehyde (23.9 g) in THF (5 mL) at −78° C., then stirred again for 15 min. The reaction mixture was then quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-[(3-formyl-pyridin-4-yl)-hydroxy-methyl]-benzonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2]>[Pd].C(O)(=O)C>[NH:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH2:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)C(C)(C)C(=O)N4CC)ccc21
Yield: 13.8 %

Procedure:
10% Palladium on carbon (0.3 g) was added to an acetic acid solution (20 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.4 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (0.19 g) as a colorless oily matter.
Reaction SMILES: O=[C:2]1[C:10]2([O:14][CH2:13][CH2:12][O:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24]OC)(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.N.[CH3:38]CO>>[CH3:38][O:24][CH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[S:15]([C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:27][C:28]4([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH2:35][N:36]=[C:2]3[C:10]3([O:14][CH2:13][CH2:12][O:11]3)[C:9]=2[CH:8]=1)(=[O:16])=[O:17]
Reactant: CCO
Reactant: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(CN)CCCCCC1
Agent: N
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C1=NCC3(CCCCCC3)CN12
Yield: 58 %

Procedure:
A solution of 1-{[2′-oxo-5′-{[(2S)-2-(methoxyoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-1′(2′H)-yl]methyl}-1-(aminomethyl)-cycloheptane (0.25 g, 0.49 mmol, 1 eq) in 2N ammonia/EtOH (5 mL) was heated in a sealed tube at 130° C. for 4 hours. After cooling, the mixture was concentrated and the residue was purified by chromatography on Biotage KP silica gel eluting with hexane/acetone (3:1) to give the title compound as an off-white solid (0.14 g, 58% yield). NMR (500 MHz, DMSO-d6): consistent. MS (API-ES+) m/z 490 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:13][O:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([CH:19]=[O:20])[CH:3]=1
Reactant: COc1cc(Br)cc2c1OCOC2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc2c1OCOC2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 31.2 g of 6-bromo-8-methoxy-4H-benzo[1,3]dioxine in 500 ml of THF there was added dropwise 55 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 20 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.28 g) as a white solid.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:27][S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:22](OCC)=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1>[CH2:3]([O:19][CH2:20][CH:21]([CH2:27][S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:22][OH:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(CO)CSCCCCCCCCCCCCCCCC
Yield: 68.1 %

Procedure:
To a slurry of 1.04 g of lithium borohydride in tetrahydrofuran at ambient temperature is added 29 g of ethyl 3-(hexadecyloxy)-2-[(hexadecylthio)methyl]propanoate followed by heating at reflux for 18 hours. The mixture is poured into water containing a small amount of acid followed by extraction with ether to give after drying and evaporation, a residue which is columned on silica gel using 30:1 hexane:ethyl acetate. Fractions containing the product are evaporated to give 18.4 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[N:28]1[N:32]=[CH:31][CH:30]=[N:29]1>>[C:26]([C:23]1[C:22]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([NH:20][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: N#Cc1csc(N)c1-n1nccn1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-n1nccn1

Procedure:
N-(4-cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.15 g, 0.56 mmol) and 5-amino-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile (0.070 g, 0.37 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min)=6.5, method [7], MS(ESI) 467.1 (M+Na). 1H NMR (CDCl3) δ 11.50 (s, 1H), 7.93-7.85 (m, 4H), 7.83 (s, 1H), 7.64 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.95 (d, J=9.7 Hz, 1H), 5.29 (s, 2H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11].[CH3:13][C:14]([CH3:21])([CH2:18][CH:19]=O)[CH2:15][CH:16]=O>>[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][N:11]1[CH:19]=[CH:18][C:14]([CH3:21])([CH3:13])[CH:15]=[CH:16]1
Reactant: CN(C)CCN
Reactant: CC(C)(CC=O)CC=O
Solvent: c1ccccc1
Product: CN(C)CCN1C=CC(C)(C)C=C1

Procedure:
In 100 ml of benzene 3.30 ml (0.03 mole) of N,N-dimethylethylenediamine was combined with 3.84 g (0.03 mole) of 3,3-dimethylglutaraldehyde under nitrogen. The reaction mixture was warmed to reflux and water azeotroped off via a Dean-Stark trap. After 15 hours the benzene was evaporated in vacuo giving 5.76 g of crude product as a brown liquid. The crude product was distilled to yield 2.41 g of the title compound as a clear liquid, bp 60° C./0.2 mm Hg.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[C:6]([NH:31]C(=O)C2C=CC=CC=2)=[N:7][C:8]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[N:9][C:10]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]#[N:20])=[CH:14][C:13]=1[CH3:21].O.[OH-].[Li+]>CC(O)C>[CH3:18][C:17]1[CH:16]=[C:15]([C:19]#[N:20])[CH:14]=[C:13]([CH3:21])[C:12]=1[O:11][C:10]1[N:9]=[C:8]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:7]=[C:6]([NH2:31])[C:5]=1[Br:4]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NC(=O)c2ccccc2)c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Temperature: 59 °C
Reaction time: 0.5 h

Procedure:
1350 ml of acetonitrile was taken into a RB flask at 27±3° C. To this was added 900 ml of IPA. To the reaction mixture 150 g of N-[5-bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]benzamide and 35.2 g of lithium hydroxide monohydrate were added and heated to 59±3° C. The reaction mixture was maintained at the same temperature for 10 hrs. After completion of the reaction, the reaction mixture was cooled to 47±3° C. and filtered. The solid was washed with acetonitrile and suck dried. The wet cake was taken into another flask to which was added 1500 ml of water, stirred for 30 mins and filtered to obtain the solid. The solid was washed with water and dried under vacuum at 73±3° C. to isolate Etravirine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:77][N:78]1[CH2:83][CH2:82][N:81]([C:84]([NH2:86])=[O:85])[CH2:80][CH2:79]1>O1CCOCC1.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].CN(C=O)C>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:86][C:84]([N:81]4[CH2:82][CH2:83][N:78]([CH3:77])[CH2:79][CH2:80]4)=[O:85])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Reactant: CN1CCN(C(N)=O)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Nc2cc(CNc3ccccc3C(=O)Nc3ccc4cn(C)nc4c3)ccn2)CC1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (110 mg, 0.25 mmol) was suspended in dioxane (3 mL) and treated consecutively with DMF (1 mL), Pd2dba3 (5 mg, 0.005 mmol), Xantphos (9 mg, 0.015 mmol), cesium carbonate (98 mg, 0.3 mmol) and 4-methyl-piperazine-1-carboxylic acid amide (184 mg, 1.3 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the volatiles were removed in vacuo and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried, filtered and concentrated. The residue was purified by chromatography using Isolute® Flash NH2 (Separtis) as stationary phase (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5) to give 4-methyl-piperazine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (28 mg, 22%) as a foam; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.11 (1H, s), 8.25 (1H, S), 8.14 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 4.43 (2H, d), 4.13 (3H, s), 3.41-3.44 (4H, m), 2.25-2.28 (4H, m), 2.17 (3H, s); m/z (ES+) 499.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].[Br:22][CH2:23][C:24](Br)=[O:25]>CC(C)=O.O>[CH3:12][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:24](=[O:25])[CH2:23][Br:22])[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a well-stirred ice-cooled mixture of 2,6-diisopropylaniline (10.0 g, 0.056 mol) in acetone (25 mL) and water (25 mL) and sodium acetate trihydrate (15.3 g, 0.112 mol), bromoacetyl bromide (17.0 g, 0.084 mol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is diluted with water (100 mL), the product filtered, washed with cold water, sodium bicarbonate solution, water, and finally with hexane. The product is dried in a vacuum at 40° C. to afford 14.5 g of the title compound as a white solid; mp I70° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C=C>CS(O)(=O)=O>[C:5]([O:4][CH2:1][CH2:2][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCCCCCCCO
Agent: CS(=O)(=O)O
Product: C=CCCCCCCCCOC(C)=O
Temperature: 30 °C
Reaction time: 18 h

Procedure:
Acetic anhydride, 54.0 grams (0.52 mole), was stirred, and one drop (catalyst) of methanesulfonic acid was added. To this was cautiously added dropwise 50.0 grams (0.32 mole) of 9-decen-1-ol. The addition caused an exothermic reaction which warmed the reaction mixture to 30° C. Upon completion of addition, the reaction mixture was warmed to 60° C. where it stirred for 18 hours. The reaction mixture was cooled and poured into 600 ml of ice/water. The mixture was stirred until the ice melted, and then the layers were separated. The aqueous layer was washed with one 300 ml portion of diethyl ether. The wash was combined with the organic layer, and the combination was washed repeatedly with aqueous 1N sodium hydroxide until the organic layer was basic. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 57 grams of 9-decenyl acetate; b.p. 93°-95° C./1.5 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[C:19]([CH3:37])=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][N:24]=[C:23]2[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].N>C1COCC1.CO.CC(O)=O>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:7]2[C:2]([NH:17][C:18]3[C:19]([CH3:37])=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][N:24]=[C:23]4[NH:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reactant: Fc1ncccc1-c1ncnc2[nH]ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 120 °C

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (78 mg, 363 μmol) and 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (100 mg, 363 μmol) in THF (4 mL) was sonicated until all solids became a fine powder. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran; 1.64 mL, 1.64 mmol) was then added dropwise with stirring (all solids dissolved and then some solid appeared again). The mixture was stirred at rt for 10 min and then heated in a microwave at 120° C. for 30 min. The mixture was poured into MeOH (10 mL) and AcOH (0.5 mL) and stirred for 10 min, then 2 M NH3 in MeOH (20 mL) was added. Solvent was removed under vacuum and the residue was purified by flash chromatography eluting with MeOH(NH3)/DCM to give 4-(8-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 470.2 [M+H]+
Reaction SMILES: [CH:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:6][CH2:5][CH2:4]CC1.[C:23](O)(=O)[CH3:24]>CO.[Pd]>[CH:8]1([C:9]2[C:10]([CH2:23][CH3:24])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[CH:13]=3)[CH2:4][CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: CC(=O)O
Reactant: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Agent: [Pd]
Solvent: CO
Product: CCc1nc2cc(OC)c(OC)cc2cc1C1CCCCC1

Procedure:
To 3-cyclohexylethynyl-6,7-dimethoxyquinoline (215 mg; 0.73 mmol) in 10 mL CH3OH and 20 mL glacial acetic acid is added 22 mg 10% Pd/C. H2 is bubbled through the reaction mixture and then filtered, evaporated to dryness and diluted with distilled water. This is then neutralized with Na2CO3, extracted with EtOAc, washed with brine, dried (MgSO4), evaporated to dryness and chromatographed with 8:2/hexane:EtOAc to obtain 3-cyclohexyl-ethyl-6,7-dimethoxyquinoline.